CN110036009A - Substituted pyrrolidines and their use in the treatment of cystic fibrosis - Google Patents
Substituted pyrrolidines and their use in the treatment of cystic fibrosis Download PDFInfo
- Publication number
- CN110036009A CN110036009A CN201780075081.3A CN201780075081A CN110036009A CN 110036009 A CN110036009 A CN 110036009A CN 201780075081 A CN201780075081 A CN 201780075081A CN 110036009 A CN110036009 A CN 110036009A
- Authority
- CN
- China
- Prior art keywords
- butyl
- tert
- methyl
- amino
- formic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 201000003883 Cystic fibrosis Diseases 0.000 title claims abstract description 20
- 238000011282 treatment Methods 0.000 title claims abstract description 5
- 150000003235 pyrrolidines Chemical class 0.000 title claims description 260
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 7
- 239000003814 drug Chemical group 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 5
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1165
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 1160
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 985
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 767
- -1 Phenyl Chemical group 0.000 claims 653
- 235000019253 formic acid Nutrition 0.000 claims 580
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 440
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 384
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 340
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 222
- 239000001294 propane Substances 0.000 claims 220
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 181
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 176
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 157
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 105
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 104
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 87
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 65
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 64
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 59
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 claims 55
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 54
- DTIXHUIVJAJESA-UHFFFAOYSA-N 5-cyclobutyl-2-methoxypyridine Chemical compound C1=NC(OC)=CC=C1C1CCC1 DTIXHUIVJAJESA-UHFFFAOYSA-N 0.000 claims 53
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 42
- 125000001072 heteroaryl group Chemical group 0.000 claims 42
- 125000000623 heterocyclic group Chemical group 0.000 claims 42
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical compound COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 claims 38
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 36
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 35
- 125000003118 aryl group Chemical group 0.000 claims 34
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims 32
- MEVKSWKZBZQIPL-UHFFFAOYSA-N 2-tert-butyl-6-methoxypyridine Chemical compound COC1=CC=CC(C(C)(C)C)=N1 MEVKSWKZBZQIPL-UHFFFAOYSA-N 0.000 claims 32
- 229910052731 fluorine Inorganic materials 0.000 claims 32
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 32
- 125000001424 substituent group Chemical group 0.000 claims 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 24
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 23
- 239000001257 hydrogen Substances 0.000 claims 23
- 229910052739 hydrogen Inorganic materials 0.000 claims 23
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 22
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 20
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 20
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 19
- 229910021529 ammonia Inorganic materials 0.000 claims 19
- 125000000217 alkyl group Chemical group 0.000 claims 18
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 17
- 150000003839 salts Chemical class 0.000 claims 17
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 13
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 12
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims 12
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 12
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims 10
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 10
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 10
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 10
- 235000010290 biphenyl Nutrition 0.000 claims 10
- 239000001301 oxygen Substances 0.000 claims 10
- 229910052760 oxygen Inorganic materials 0.000 claims 10
- HXWJVGQRJZZUOD-UHFFFAOYSA-N (5-tert-butyl-2-methoxyphenyl)methanamine Chemical compound COC1=CC=C(C(C)(C)C)C=C1CN HXWJVGQRJZZUOD-UHFFFAOYSA-N 0.000 claims 9
- 239000011737 fluorine Substances 0.000 claims 9
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims 9
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 9
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims 8
- 229950011148 cyclopropane Drugs 0.000 claims 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 8
- XJLFOSWEBBQLFX-UHFFFAOYSA-N 2-methoxyquinoline Chemical compound C1=C[CH]C2=NC(OC)=C=CC2=C1 XJLFOSWEBBQLFX-UHFFFAOYSA-N 0.000 claims 7
- LTOZBOCLXXPCOF-UHFFFAOYSA-N 5-tert-butyl-2-methoxypyridine Chemical compound COC1=CC=C(C(C)(C)C)C=N1 LTOZBOCLXXPCOF-UHFFFAOYSA-N 0.000 claims 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 7
- 150000002240 furans Chemical class 0.000 claims 7
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims 7
- ZZMSDLWVAMNVOD-UHFFFAOYSA-N 1-phenylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1CCCN1C1=CC=CC=C1 ZZMSDLWVAMNVOD-UHFFFAOYSA-N 0.000 claims 6
- PORGLLGXCAQORO-UHFFFAOYSA-N 3-bromo-2-methoxypyridine Chemical compound COC1=NC=CC=C1Br PORGLLGXCAQORO-UHFFFAOYSA-N 0.000 claims 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 6
- 206010011224 Cough Diseases 0.000 claims 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 6
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 claims 6
- 125000000304 alkynyl group Chemical group 0.000 claims 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 6
- 150000003053 piperidines Chemical class 0.000 claims 6
- 229940124597 therapeutic agent Drugs 0.000 claims 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims 5
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims 5
- LUZDYPLAQQGJEA-UHFFFAOYSA-N 2-Methoxynaphthalene Chemical compound C1=CC=CC2=CC(OC)=CC=C21 LUZDYPLAQQGJEA-UHFFFAOYSA-N 0.000 claims 5
- YUFQWPLVENFXJW-UHFFFAOYSA-N 5-cyclopropyl-2-methoxypyridine Chemical compound C1=NC(OC)=CC=C1C1CC1 YUFQWPLVENFXJW-UHFFFAOYSA-N 0.000 claims 5
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims 5
- AHIBWURJLGCHAY-UHFFFAOYSA-N [S].C1=CC=CC=C1 Chemical compound [S].C1=CC=CC=C1 AHIBWURJLGCHAY-UHFFFAOYSA-N 0.000 claims 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 5
- UJMGZPCKYHBCKU-UHFFFAOYSA-N 2,2-dimethyl-2,3-dihydrobenzofuran Chemical class C1=CC=C2OC(C)(C)CC2=C1 UJMGZPCKYHBCKU-UHFFFAOYSA-N 0.000 claims 4
- ARGCQEVBJHPOGB-UHFFFAOYSA-N 2,5-dihydrofuran Chemical compound C1OCC=C1 ARGCQEVBJHPOGB-UHFFFAOYSA-N 0.000 claims 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 4
- 241000790917 Dioxys <bee> Species 0.000 claims 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 4
- 239000001273 butane Substances 0.000 claims 4
- 229910052799 carbon Inorganic materials 0.000 claims 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims 4
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 4
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- SUHYUUVUQGJUJC-UHFFFAOYSA-N 2-cyclopropylpyridine Chemical compound C1CC1C1=CC=CC=N1 SUHYUUVUQGJUJC-UHFFFAOYSA-N 0.000 claims 3
- 125000002252 acyl group Chemical group 0.000 claims 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims 3
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 claims 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- BTQZKHUEUDPRST-UHFFFAOYSA-N 1-fluoro-3-methylbenzene Chemical compound CC1=CC=CC(F)=C1 BTQZKHUEUDPRST-UHFFFAOYSA-N 0.000 claims 2
- NLHYNCJBWXKZGP-UHFFFAOYSA-N 1-methyl-5-phenylpyrazole Chemical class CN1N=CC=C1C1=CC=CC=C1 NLHYNCJBWXKZGP-UHFFFAOYSA-N 0.000 claims 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- CSJLJSGWKXPGRN-UHFFFAOYSA-N 2,4-dimethoxypyridine Chemical compound COC1=CC=NC(OC)=C1 CSJLJSGWKXPGRN-UHFFFAOYSA-N 0.000 claims 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 2
- GYXLBTAQOUCOCP-UHFFFAOYSA-N 2-tert-butyl-4-methoxypyrimidine Chemical compound COC1=CC=NC(C(C)(C)C)=N1 GYXLBTAQOUCOCP-UHFFFAOYSA-N 0.000 claims 2
- BBVONLXDPCBKAJ-UHFFFAOYSA-N 2-tert-butyl-5-methoxypyridine Chemical compound COC1=CC=C(C(C)(C)C)N=C1 BBVONLXDPCBKAJ-UHFFFAOYSA-N 0.000 claims 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims 2
- UDIWHZDIMFRYII-UHFFFAOYSA-N 5-(2-fluorophenyl)-2-methoxypyridine Chemical compound C1=NC(OC)=CC=C1C1=CC=CC=C1F UDIWHZDIMFRYII-UHFFFAOYSA-N 0.000 claims 2
- ZEPFMUDJBSAEJR-UHFFFAOYSA-N 5-chloro-2,3-dihydro-1h-indene Chemical class ClC1=CC=C2CCCC2=C1 ZEPFMUDJBSAEJR-UHFFFAOYSA-N 0.000 claims 2
- KNULMJDSQCYXQL-UHFFFAOYSA-N 5-cyclohexyl-2-methoxypyridine Chemical compound C1=NC(OC)=CC=C1C1CCCCC1 KNULMJDSQCYXQL-UHFFFAOYSA-N 0.000 claims 2
- ZRNVDOJOQQRFAF-UHFFFAOYSA-N COC1=CC=CC(=N1)C1CCC1 Chemical compound COC1=CC=CC(=N1)C1CCC1 ZRNVDOJOQQRFAF-UHFFFAOYSA-N 0.000 claims 2
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical class CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 2
- 150000001336 alkenes Chemical class 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 2
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 claims 2
- QEGNUYASOUJEHD-UHFFFAOYSA-N gem-dimethylcyclohexane Natural products CC1(C)CCCCC1 QEGNUYASOUJEHD-UHFFFAOYSA-N 0.000 claims 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 2
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 239000012744 reinforcing agent Substances 0.000 claims 2
- SJUKJZSTBBSGHF-UHFFFAOYSA-N (2,4-dichlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1Cl SJUKJZSTBBSGHF-UHFFFAOYSA-N 0.000 claims 1
- PXJACNDVRNAFHD-UHFFFAOYSA-N (2-methoxyphenyl)methanamine Chemical compound COC1=CC=CC=C1CN PXJACNDVRNAFHD-UHFFFAOYSA-N 0.000 claims 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 claims 1
- QXALUNHYJJONQH-UHFFFAOYSA-N 1,1,1-trifluoro-2-methylpropane Chemical compound CC(C)C(F)(F)F QXALUNHYJJONQH-UHFFFAOYSA-N 0.000 claims 1
- AXWRKAANHAVLRK-UHFFFAOYSA-N 1-cyclobutylpyrazole Chemical class C1CCC1N1N=CC=C1 AXWRKAANHAVLRK-UHFFFAOYSA-N 0.000 claims 1
- YWLZMOUAZWHRFP-UHFFFAOYSA-N 1-cyclopropylpyrazole Chemical class C1CC1N1N=CC=C1 YWLZMOUAZWHRFP-UHFFFAOYSA-N 0.000 claims 1
- XMOWAIVXKJWQBJ-UHFFFAOYSA-N 1-ethyl-2-methylindole Chemical compound C1=CC=C2N(CC)C(C)=CC2=C1 XMOWAIVXKJWQBJ-UHFFFAOYSA-N 0.000 claims 1
- FLGIATBXANRPOT-UHFFFAOYSA-N 1-methoxy-3-(4-methoxyphenyl)benzene Chemical compound C1=CC(OC)=CC=C1C1=CC=CC(OC)=C1 FLGIATBXANRPOT-UHFFFAOYSA-N 0.000 claims 1
- AQQUNJMVAKJGKR-UHFFFAOYSA-N 1-methyl-3-phenylpyrazole Chemical class CN1C=CC(C=2C=CC=CC=2)=N1 AQQUNJMVAKJGKR-UHFFFAOYSA-N 0.000 claims 1
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical class C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims 1
- DVVGIUUJYPYENY-UHFFFAOYSA-N 1-methylpyridin-2-one Chemical compound CN1C=CC=CC1=O DVVGIUUJYPYENY-UHFFFAOYSA-N 0.000 claims 1
- QYRXZLMOIBPKTJ-UHFFFAOYSA-N 1-phenylpyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1C1=CC=CC=C1 QYRXZLMOIBPKTJ-UHFFFAOYSA-N 0.000 claims 1
- MCUPBIBNSTXCPQ-UHFFFAOYSA-N 1-tert-butyl-4-methoxybenzene Chemical compound COC1=CC=C(C(C)(C)C)C=C1 MCUPBIBNSTXCPQ-UHFFFAOYSA-N 0.000 claims 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 1
- MREIFUWKYMNYTK-UHFFFAOYSA-N 1H-pyrrole Chemical class C=1C=CNC=1.C=1C=CNC=1 MREIFUWKYMNYTK-UHFFFAOYSA-N 0.000 claims 1
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical class C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 claims 1
- XNOGONRNEMKHIO-UHFFFAOYSA-N 2,2,6,6-tetramethyloxane Chemical compound CC1(C)CCCC(C)(C)O1 XNOGONRNEMKHIO-UHFFFAOYSA-N 0.000 claims 1
- DGCOGZQDAXUUBY-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole Chemical compound C1=CC=C2OC(F)(F)OC2=C1 DGCOGZQDAXUUBY-UHFFFAOYSA-N 0.000 claims 1
- SWZUJPXFLKZGLI-UHFFFAOYSA-N 2,2-dimethyloxane Chemical compound CC1(C)CCCCO1 SWZUJPXFLKZGLI-UHFFFAOYSA-N 0.000 claims 1
- OBSLLHNATPQFMJ-UHFFFAOYSA-N 2,4-Dimethylthiazole Chemical class CC1=CSC(C)=N1 OBSLLHNATPQFMJ-UHFFFAOYSA-N 0.000 claims 1
- IBTGEEMBZJBBSH-UHFFFAOYSA-N 2,6-dimethoxypyridine Chemical compound COC1=CC=CC(OC)=N1 IBTGEEMBZJBBSH-UHFFFAOYSA-N 0.000 claims 1
- PDOWLYNSFYZIQX-UHFFFAOYSA-N 2-bromo-3-methoxypyridine Chemical compound COC1=CC=CN=C1Br PDOWLYNSFYZIQX-UHFFFAOYSA-N 0.000 claims 1
- CCVNZKGBNUPYPG-UHFFFAOYSA-N 2-chloro-3-methoxypyridine Chemical compound COC1=CC=CN=C1Cl CCVNZKGBNUPYPG-UHFFFAOYSA-N 0.000 claims 1
- QRXBTPFMCTXCRD-UHFFFAOYSA-N 2-chloropyridine-4-carbonitrile Chemical compound ClC1=CC(C#N)=CC=N1 QRXBTPFMCTXCRD-UHFFFAOYSA-N 0.000 claims 1
- DEMJOLRJLACBRX-UHFFFAOYSA-N 2-chloropyridine-4-carboxamide Chemical compound NC(=O)C1=CC=NC(Cl)=C1 DEMJOLRJLACBRX-UHFFFAOYSA-N 0.000 claims 1
- KJECFWJLLPVJHW-UHFFFAOYSA-N 2-cyclobutyl-5-methoxypyridine Chemical compound N1=CC(OC)=CC=C1C1CCC1 KJECFWJLLPVJHW-UHFFFAOYSA-N 0.000 claims 1
- IFRMRTJBELSCHL-UHFFFAOYSA-N 2-fluoro-4-methylquinoline Chemical compound C1=CC=C2C(C)=CC(F)=NC2=C1 IFRMRTJBELSCHL-UHFFFAOYSA-N 0.000 claims 1
- ZXMPSTMIJQZYLV-UHFFFAOYSA-N 2-methyl-1,2-dihydrophthalazin-1-one Chemical class C1=CC=C2C(=O)N(C)N=CC2=C1 ZXMPSTMIJQZYLV-UHFFFAOYSA-N 0.000 claims 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- AMEALNUOZWKTJR-UHFFFAOYSA-N 2-tert-butyl-6-chloropyridine Chemical compound CC(C)(C)C1=CC=CC(Cl)=N1 AMEALNUOZWKTJR-UHFFFAOYSA-N 0.000 claims 1
- RIYVWXMPEVWCSH-UHFFFAOYSA-N 2-tert-butylpyrazole-3-carbonitrile Chemical class CC(C)(C)N1N=CC=C1C#N RIYVWXMPEVWCSH-UHFFFAOYSA-N 0.000 claims 1
- FICAQKBMCKEFDI-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole Chemical compound CC=1C=C(C)ON=1 FICAQKBMCKEFDI-UHFFFAOYSA-N 0.000 claims 1
- WKGHUAZJNBXABN-UHFFFAOYSA-N 3-bromo-2-chloro-6-methyl-5-nitropyridine Chemical compound CC1=NC(Cl)=C(Br)C=C1[N+]([O-])=O WKGHUAZJNBXABN-UHFFFAOYSA-N 0.000 claims 1
- MSICGKUDCSUMJZ-UHFFFAOYSA-N 3-chloro-2-methoxypyridine Chemical compound COC1=NC=CC=C1Cl MSICGKUDCSUMJZ-UHFFFAOYSA-N 0.000 claims 1
- PWRBCZZQRRPXAB-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=CN=C1 PWRBCZZQRRPXAB-UHFFFAOYSA-N 0.000 claims 1
- VOXFISDIRIAWCW-UHFFFAOYSA-N 3-fluoro-2-methoxypyridine Chemical compound COC1=NC=CC=C1F VOXFISDIRIAWCW-UHFFFAOYSA-N 0.000 claims 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- GLXIOXNPORODGG-UHFFFAOYSA-N 3-methyl-2,3-dihydrofuran Chemical class CC1COC=C1 GLXIOXNPORODGG-UHFFFAOYSA-N 0.000 claims 1
- LLWFWIZOFFLRKC-UHFFFAOYSA-N 3-phenylmethoxypyridine Chemical compound C=1C=CC=CC=1COC1=CC=CN=C1 LLWFWIZOFFLRKC-UHFFFAOYSA-N 0.000 claims 1
- CKFUXDQSNIACCU-UHFFFAOYSA-N 3-tert-butyl-4-[(2-chlorophenyl)methylamino]-1-(2-cyclopentylacetyl)-5-phenylpyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)C1C(N(C(C1NCC1=C(C=CC=C1)Cl)C1=CC=CC=C1)C(CC1CCCC1)=O)C(=O)O CKFUXDQSNIACCU-UHFFFAOYSA-N 0.000 claims 1
- BZIDYPIJVCEUIB-UHFFFAOYSA-N 4,6-dimethylpyridine-3-carbonitrile Chemical class CC1=CC(C)=C(C#N)C=N1 BZIDYPIJVCEUIB-UHFFFAOYSA-N 0.000 claims 1
- RWGAUBPDRQJOQL-UHFFFAOYSA-N 4-(2-methoxyphenyl)oxane Chemical compound COc1ccccc1C1CCOCC1 RWGAUBPDRQJOQL-UHFFFAOYSA-N 0.000 claims 1
- KZSTZXYJQSXEBP-UHFFFAOYSA-N 4-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=C[C]=NC=C1 KZSTZXYJQSXEBP-UHFFFAOYSA-N 0.000 claims 1
- UHAFYHPCGMJBEJ-UHFFFAOYSA-N 4-chloro-1,3-benzodioxole Chemical compound ClC1=CC=CC2=C1OCO2 UHAFYHPCGMJBEJ-UHFFFAOYSA-N 0.000 claims 1
- KLJGSQVYUGQOAW-UHFFFAOYSA-N 4-chloro-6-methoxypyrimidine Chemical compound COC1=CC(Cl)=NC=N1 KLJGSQVYUGQOAW-UHFFFAOYSA-N 0.000 claims 1
- PVMNPAUTCMBOMO-UHFFFAOYSA-N 4-chloropyridine Chemical compound ClC1=CC=NC=C1 PVMNPAUTCMBOMO-UHFFFAOYSA-N 0.000 claims 1
- NBAWYUCPNKZTER-UHFFFAOYSA-N 4-ethoxyquinoline Chemical compound C1=CC=C2C(OCC)=CC=NC2=C1 NBAWYUCPNKZTER-UHFFFAOYSA-N 0.000 claims 1
- XQABVLBGNWBWIV-UHFFFAOYSA-N 4-methoxypyridine Chemical compound COC1=CC=NC=C1 XQABVLBGNWBWIV-UHFFFAOYSA-N 0.000 claims 1
- PENVYHXKYYCYML-UHFFFAOYSA-N 4-methoxypyrimidine Chemical compound COC1=CC=NC=N1 PENVYHXKYYCYML-UHFFFAOYSA-N 0.000 claims 1
- JYQMTEGQTKXOTK-UHFFFAOYSA-N 4-methoxyquinoline-3-carbonitrile Chemical compound C1=CC=C2C(OC)=C(C#N)C=NC2=C1 JYQMTEGQTKXOTK-UHFFFAOYSA-N 0.000 claims 1
- ZWXIXHAKODDHHY-UHFFFAOYSA-N 4-methyl-6-(trifluoromethyl)pyrimidine Chemical compound CC1=CC(C(F)(F)F)=NC=N1 ZWXIXHAKODDHHY-UHFFFAOYSA-N 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- MKGKOBPBZKTVNS-UHFFFAOYSA-N 5-benzyl-2-methoxypyridine Chemical compound C1=NC(OC)=CC=C1CC1=CC=CC=C1 MKGKOBPBZKTVNS-UHFFFAOYSA-N 0.000 claims 1
- ODQPZHOXLYATLC-UHFFFAOYSA-N 5-chloro-1,3-benzodioxole Chemical compound ClC1=CC=C2OCOC2=C1 ODQPZHOXLYATLC-UHFFFAOYSA-N 0.000 claims 1
- WJRKNLONLOMALV-UHFFFAOYSA-N 5-chloropyridine Chemical compound ClC1=C=NC=C[CH]1 WJRKNLONLOMALV-UHFFFAOYSA-N 0.000 claims 1
- GIPOQOUSJKAZMC-UHFFFAOYSA-N 5-methyl-1-phenylpyrazole Chemical class CC1=CC=NN1C1=CC=CC=C1 GIPOQOUSJKAZMC-UHFFFAOYSA-N 0.000 claims 1
- YGHFBOUZWKVYLL-UHFFFAOYSA-N 6-anilinopyridine-3-carbonitrile Chemical compound N1=CC(C#N)=CC=C1NC1=CC=CC=C1 YGHFBOUZWKVYLL-UHFFFAOYSA-N 0.000 claims 1
- GBSHPLZUEUOEQD-UHFFFAOYSA-N 6-chloro-4H-pyridin-3-one Chemical compound ClC=1N=CC(CC=1)=O GBSHPLZUEUOEQD-UHFFFAOYSA-N 0.000 claims 1
- ORIQLMBUPMABDV-UHFFFAOYSA-N 6-chloropyridine-3-carbonitrile Chemical compound ClC1=CC=C(C#N)C=N1 ORIQLMBUPMABDV-UHFFFAOYSA-N 0.000 claims 1
- PBLOYQAQGYUPCM-UHFFFAOYSA-N 6-methylpyridine-3-carbonitrile Chemical compound CC1=CC=C(C#N)C=N1 PBLOYQAQGYUPCM-UHFFFAOYSA-N 0.000 claims 1
- HHSSILNQLVHEJC-PJEZFMNTSA-N C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(=O)C1CC11CCOCC1)C(=O)O Chemical compound C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(=O)C1CC11CCOCC1)C(=O)O HHSSILNQLVHEJC-PJEZFMNTSA-N 0.000 claims 1
- JGKHCUHKXOFIAU-MJVFHSFESA-N C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(=O)C1CN(C(C1)=O)C1CC1)C(=O)O Chemical compound C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(=O)C1CN(C(C1)=O)C1CC1)C(=O)O JGKHCUHKXOFIAU-MJVFHSFESA-N 0.000 claims 1
- PLFGWFTXMVHXFU-AFSDOIIVSA-N C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(=O)[C@@H]1[C@H]2CC[C@@H](C1)O2)C(=O)O Chemical compound C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(=O)[C@@H]1[C@H]2CC[C@@H](C1)O2)C(=O)O PLFGWFTXMVHXFU-AFSDOIIVSA-N 0.000 claims 1
- MDUYDNAFVSAZOC-WOHIDQGGSA-N C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(CC(CC)(C)O)=O)C(=O)O Chemical compound C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C(CC(CC)(C)O)=O)C(=O)O MDUYDNAFVSAZOC-WOHIDQGGSA-N 0.000 claims 1
- WMFIKRSJYPEOFX-XDIGFQIYSA-N C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C([C@@H](OC)C1=CC(=C(C=C1)F)F)=O)C(=O)O Chemical compound C(C)(C)(C)[C@@H]1[C@H](N([C@H]([C@H]1NCC1=C(C=CC(=C1)C(C)(C)C)OC)C1=CC=CC=C1)C([C@@H](OC)C1=CC(=C(C=C1)F)F)=O)C(=O)O WMFIKRSJYPEOFX-XDIGFQIYSA-N 0.000 claims 1
- HREPYCUGXIOAGO-KRCBVYEFSA-N C(C1=CC=CC=C1)(=O)N1[C@@H]([C@H]([C@@H]([C@@H]1C1=CC=CC=C1)NCC1=C(C=CC(=C1)C(C)(C)C)OC)C(C)(C)C)C(=O)O Chemical compound C(C1=CC=CC=C1)(=O)N1[C@@H]([C@H]([C@@H]([C@@H]1C1=CC=CC=C1)NCC1=C(C=CC(=C1)C(C)(C)C)OC)C(C)(C)C)C(=O)O HREPYCUGXIOAGO-KRCBVYEFSA-N 0.000 claims 1
- ZJEIQAVSKHHECZ-UHFFFAOYSA-N CCCCC[O] Chemical compound CCCCC[O] ZJEIQAVSKHHECZ-UHFFFAOYSA-N 0.000 claims 1
- LKSYGCFKDCCDNY-UHFFFAOYSA-N Cl[N+]1=CC(=CC2=CC=CC=C12)CC Chemical compound Cl[N+]1=CC(=CC2=CC=CC=C12)CC LKSYGCFKDCCDNY-UHFFFAOYSA-N 0.000 claims 1
- JXSLVGSMJBLCMS-YDPTYEFTSA-N O1C=C(C2=C1C=CC=C2)C(=O)N1[C@@H]([C@H]([C@@H]([C@@H]1C1=CC=CC=C1)NCC1=C(C=CC(=C1)C(C)(C)C)OC)C(C)(C)C)C(=O)O Chemical compound O1C=C(C2=C1C=CC=C2)C(=O)N1[C@@H]([C@H]([C@@H]([C@@H]1C1=CC=CC=C1)NCC1=C(C=CC(=C1)C(C)(C)C)OC)C(C)(C)C)C(=O)O JXSLVGSMJBLCMS-YDPTYEFTSA-N 0.000 claims 1
- GKXVJHDEWHKBFH-UHFFFAOYSA-N [2-(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC=CC=C1CN GKXVJHDEWHKBFH-UHFFFAOYSA-N 0.000 claims 1
- MQTBAGAVFDZXKF-UHFFFAOYSA-N [2-fluoro-4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1F MQTBAGAVFDZXKF-UHFFFAOYSA-N 0.000 claims 1
- BLQGRYYLPWCHMA-UHFFFAOYSA-N [4-fluoro-2-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(F)C=C1C(F)(F)F BLQGRYYLPWCHMA-UHFFFAOYSA-N 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- VQGHOUODWALEFC-UHFFFAOYSA-N alpha-Phenylpyridine Natural products C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims 1
- 238000012937 correction Methods 0.000 claims 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims 1
- JVZRCNQLWOELDU-UHFFFAOYSA-N gamma-Phenylpyridine Natural products C1=CC=CC=C1C1=CC=NC=C1 JVZRCNQLWOELDU-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical class C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims 1
- 150000002921 oxetanes Chemical class 0.000 claims 1
- 229960003540 oxyquinoline Drugs 0.000 claims 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 claims 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 1
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 description 11
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000032258 transport Effects 0.000 description 8
- 108010078791 Carrier Proteins Proteins 0.000 description 5
- 102000014914 Carrier Proteins Human genes 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003792 electrolyte Substances 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 238000012252 genetic analysis Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 108091006515 Anion channels Proteins 0.000 description 1
- 102000037829 Anion channels Human genes 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 241000218636 Thuja Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000004656 cell transport Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses compounds having formula (I), wherein R1、R2、R2A、R3、R3A、R4、R4AAnd R5Is as defined herein. The present invention relates to compounds and their use for the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising them and methods of treating cystic fibrosis by administering a compound of the invention.
Description
Cross reference to related applications
This application claims the priority for the U.S. Provisional Application No. 62/405,598 submitted on October 7th, 2016, go out
In all purposes to be incorporated by herein.
Background technique
Technical field
The present invention relates to the pyridine compounds being substituted, and are the tune that CF transmembrane conductance adjusts (CFTR) albumen
Agent is saved, and can be used for treating the disease and illness for being mediated and being adjusted by CFTR.The invention further relates to contain chemical combination of the present invention
Composition, preparation method and the treatment method using it of object.
Description of related art
Abc transport albumen is to adjust turning for miscellaneous pharmacological agents (such as drug, xenobiotics, anion etc.)
The homologous protein called membrane transporters family of fortune, these transport proteins combine for given activity and use cell atriphos
(ATP).It was found that some in these transport proteins make malignant tumor cells fight chemotherapeutics, Mdr-p is served as (such as
MDR1-P glycoprotein or Mdr-p MRP 1).So far, 48 kinds of abc transport albumen have been identified, its sequence is based on
Identity and function are divided into 7 families.
Abc transport albumen provides the guarantor of confrontation hostile environment compound by adjusting internal a variety of important physiological actions
Shield, and therefore represent for treat with transport protein defect, outside cell drug transhipment related disease and other wherein
The adjusting of abc transport protein active may be the important potential drug target of beneficial disease.
The anion channel CFTR that cAMP/ATP tune is situated between be one of abc transport protein family usually related with disease at
Member, expression is in various cell types (including absorbability and secretory epithelial cell), and wherein it is logical to regulate and control anion cross-film for it
The activity of amount and other ion channels and protein.CFTR activity in epithelial cell (includes breathing through body to maintenance
And digestion tissue) most important (Quinton, P.M., 1990.Cystic the fibrosis:a disease of electrolyte transport
In electrolyte transport. [cystic fibrosis: electrolyte transport disease] FASEB J.4,2709-2717).
The gene of identifier number CFTR and be sequenced (Kerem, B., Rommens, J.M., Buchanan, JA.,
Markiewicz, D., Cox, T.K., Chakravarti, A., Buchwald, M., Tsui, L.C.,
1989.Identification of the cystic fibrosis gene:genetic analysis. [cystic fibrosis
Identified for genes: genetic analysis] Science [science] 245,1073-1080).CFTR includes to the series connection weight by transmembrane domain
About 1480 amino acid that the protein of complex sequences composition is encoded, each transmembrane domain include six transbilayer helixes and core
Thuja acid binding structural domain.This adjusts the connection of (R)-structural domain by big polarity to transmembrane domain, and being somebody's turn to do (R)-structural domain has tune
Save multiple phosphorylation sites of channel activity and cell transport.
Cystic fibrosis (CF) is thus induced in gene caused by the defect of the mutation in CFTR.Cystic fibrosis is people
The most common fatal genetic disease in class, and influence about 0.04% white man (Bobadilla, J.L., Macek, M., Jr,
Fine, J.P., Farrell, P.M., 2002.Cystic fibrosis:a worldwide analvsis of CFTR
Mutatiohs--correlation with incidence data and application to screening. [capsule
Fibrosis: the whole world analysis of CFTR mutation -- the relevance with disease incidence data and application screening] [mankind are prominent by Hum.Mutat.
Become] 19,575-606.doi:10.1002/humu.10041), for example, there are about a babies in every 2500 babies in the U.S.
It is affected, and up to 10,000,000 people carry single copy with defective gene and have no obvious disease effector；In addition, carrying
The subject of gene list copy shows increased resistance to cholera and to the dehydration as caused by diarrhea.This effect may solve
The higher situation of frequency of CF gene in crowd is released.
In contrast, the individual with the double copies of CF related gene is by weak caused by CF and lethal effect, comprising slow
Property pulmonary infection.
In cystic fibrosis patient, the mutation of endogenous respiratory system epithelium CFTR cannot be assigned in lung and its hetero-organization
Epithelial cell chloride and bicarbonate permeability, so as to cause top anion (apical anion) secrete reduce and from
Son and fluid transport are interrupted.This decline of anion transport leads to increased mucus and pathogen accumulation in lung, to cause
Eventually lead to the microorganism infection of CF death.
In addition to respiratory disorder, CF patient also suffers from gastrointestinal problems and pancreatic insufficiency, if not treated, can cause
It is dead.In addition, the fertility decline of the female subjects with cystic fibrosis, and suffer from the male sterility of cystic fibrosis.
By the sequence of the cftr gene of CF chromosome analyzed and identified it is a variety of cause disease mutation (Kerem,
B., Rommens, J.M., Buchanan, J.A., Markiewicz, D., Cox, T.K., Chakravarti, A., Buchwald,
M., Tsui, L.C., 1989.Identification of the cystic fibrosis gene:genetic
Analysis. [cystic fibrosis gene identification: genetic analysis] Science [science] 245,1073-1080).The most common CF
It is mutated and the F508delCFTR occurred in about 70% cystic fibrosis case (is present in about 90% CF patient
At least one allele in) comprising phenylalanine 508 single amino acids lack.This missing can prevent nascent protein correct
It folds, which cannot then leave endoplasmic reticulum (ER) and be delivered to plasma membrane, and then degradation rapidly.Accordingly, there exist in
Port number in film is far below the port number in the cell of expression wild type CFTR.Other than impaired transport, mutation is led
Cause channel gating deficit.In fact, even if making F508delCFTR reach cell membrane plasmapheresis (herein by (27 DEG C) of low temperature rescues
It can be used as cAMP activation chloride channel and plays a role), but compared with WT-CFTR, activity significant decrease (Pasyk,
E.A., Foskett, J.K., 1995.Mutant (F508delCFTR) Cystic Fibrosis Transmembrane
Conductance Regulator Cl channel is functional when retained in Endoplasmic
Reticulum of mammalian cells. [when being retained in mammalian cell endoplasmic reticulum, mutant
(F508delCFTR) cystic fibrosis transmembrane conductance regulator Cl-Channel has functionality] J.Biol.Chem. [bioid
Learn magazine] 270,12347-12350).
Also identify other mutation with lower incidence for changing channel adjusting or channel conductance.It is adjusted in channel prominent
In the case where variant, the protein of mutation suitably transported and be positioned at plasma membrane but cannot be activated or cannot function as chlorine from
Subchannel plays a role (such as missense mutation in nucleotide binding domain), these mutation examples be G551D,
G178R and G1349D.The mutation for influencing chloride conduction, which has, is correctly transported to cell membrane but generates reduced chloride
The example of the CFTR albumen (such as missense mutation in transmembrane domain) of stream, these mutation is R117H and R334W.
Other than cystic fibrosis, CFTR Active Regulation may to not directly by CFTR be mutated caused by other diseases,
Such as chronic obstructive pulmonary disease (COPD), scheroma and Sjogren syndrome (Syndrome) beneficial.
COPD is characterized by progressive caused by Polyblennia, bronchiolitis and pulmonary emphysema and irreversible
Property flow limitation.In COPD the impaired potential treatment of common Polyblennia and mucociliary clearance can be using
The activator of saltant type or wild type CFTR.Specifically, the anion secretion increase across CFTR can promote fluid delivery and arrive
With hydrated mucilage and optimize fine all fluid viscosity in Airway surface liquid.The mucociliary clearance of resulting enhancing will have
Help mitigate symptom relevant to COPD.
Scheroma is characterized in that tear generates and reduces and tear film lipid, protein and mucin spectrum exception.Many factors can
Cause scheroma, some factors include age, arthritis, Lasik ophthalmologic operation, chemistry/thermal damage, drug, allergy and such as
The diseases such as cystic fibrosis and Sjogren syndrome.Via CFTR increase anion secretion can be enhanced from endothelial cell and
Eye circumference encloses eccrine fluid delivery, and finally improves cornea aquation, to help to mitigate symptom relevant to scheroma.
Sjogren syndrome is autoimmune disease, and the body of gland that wherein immune system generates moisture to inside of human body damages, including
Eyes, oral cavity, skin, respiratory tissues, liver, vagina and enteron aisle.The following symptom includes dry eyes, oral cavity and vagina disease
Disease, together with pulmonary disease.Sjogren syndrome also with rheumatoid arthritis, systemic loupus erythematosus, systemic sclerosis and more
Myositis/dermatomyositis is related.The reason of disease is considered as being present in defective protein import, and therapeutic choice is that have
Limit.Therefore, adjusting CFTR activity can contribute to moisturizing Different Organs and helps to promote related symptoms.
In addition to CF, have been displayed by F508delCFTR induction defective protein import be various other diseases (especially
Wherein the functional defect of endoplasmic reticulum (ER) can prevent CFTR albumen from leaving the protein of cell, and/or degradable false folding
Disease) it is potential basis (Morello, J.-P., Bouvier, M.,U.E., Bichet, D.G.,
2000.Pharmacological chaperones:a new twist on receptor folding. [pharmacological chaperone:
The new situation that receptor folds] Trends Pharmacol.Sci. [Trends Pharmacol. Sci] 21,466-469.doi:10.1016/
S0165-6147(00)01575-3；Shastry, B.S., 2003.Neurodegenerative disorders of
Protein aggregation. [neurodegenerative disorders of albumen aggregation] Neurochem.Int. [international neurochemistry] 43,
1-7.doi:10.1016/S0197-0186 (02) 00196-1；Zhang, W., Fujii, N., Naren, A.P.,
2012.Recent advances and new perspectives in targeting CFTR for therapy of
[targeting CFTR is for treating by cystic fibrosis and enterotoxin-induced secretory diarrheas.
The latest development and new prospect of the secretory diarrhea of cystic fibrosis and enterotoxin induction] (Future Med.Chem. [future doctor
Medicine chemistry] 4,329-345.doi:10.4155/fmc.12.1).
Many genetic diseases are related with the defective ER processing for using defect observed by CFTR equivalent in CF, example
As 1 type sugar locks abnormal (glycanosis) CDG, hereditary emphysema (α -1- antitrypsin (PiZ variant)), congenital thyroid gland
Hyperfunction, osteogenesis imperfecta (I type, II type or IV procollagen type), hereditary hypofibrinogenemia (fibrinogen),
ACT defect (alpha-1-antichymotrypsin analogues), diabetes insipidus (DI), neurohypophysis DI (pitressin hormone N2- receptor), kidney source property
DI (aquaporin II), charcot-Marie-Tooth syndrome (Charcot-Marie Tooth syndrome) (periphery myelin
4 protein 22), pelizaeus-Merzbacher disease (Pelizaeus-Merzbacher disease), neurodegenerative disease (such as Alzheimer
Family name's disease) (APP and presenilin), Parkinson's disease, amyotrophic lateral sclerosis, stein-leventhal syndrome, Pi Keshi
Sick, several polyglutamyl amine neuropathic conditions (such as Huntington's disease), the spinocebellar ataxia of I type, spinal bulbar flesh
Meat atrophy, dentation rubrum globus pallidus muscular atrophy and myotonia atrophica and spongiform encephalopathy (such as heredity gram
Creutzfeldt-Jakob disease (hereditary Creutzfeldt-Jakob disease)) (prion protein processing lacks
Fall into), Fabry disease (Fabry disease) (lysosome alpha-galactosidase A), lattice Stedman-Astrid Strauss receive syndrome
(Straussler-Scheinker syndrome), chronic obstructive pulmonary disease (COPD), scheroma and Sjogren syndrome.
Other than the activity of up-regulation CFTR, it can be beneficial to secrete by the reduction of anion secretion caused by CFTR regulator
Property diarrhea treatment, wherein epithelial water transport dramatically increases due to the chloride transport of sercretogogue activation.The mechanism is related to
The raising of cAMP and the stimulation of CFTR.
No matter the cause of disease, all see that excess chlorine compound is transported in all diarrhea, and dehydration, acid poisoning, life can be caused
It is long impaired and dead.Acute diarrhea and chronic diarrhea are still global significant medical problem, and be it is underfed it is important because
Element can cause dead (5,000,000 death/years) at 5 years old in children below.In addition, suffering from chronic inflammatory bowel disease (IBD)
And/or in the patient of acquired immunodeficiency syndrome (AIDS), diarrhea is dangerous disorders.
It is therefore desirable to be able to adjust the compounds of CFTR.Specifically, the present invention discloses can serve as controlling
Treat the compound of the CFTR regulator of cystic fibrosis.The present invention also provides be used to prepare the method for these compounds, include
The pharmaceutical composition of these compounds and the method that cystic fibrosis is treated by giving the compound of the present invention.
Summary of the invention
In one aspect, the present invention provides the compounds with formula (I)
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl and C3-C6Naphthenic base；
R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl；Its
In the R3 C1-C6The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of:
C1-C6Alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3 C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl
The substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkane
Oxygroup, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And
R3AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；Wherein by R3And R3AAnd attached by them
The C that carbon is formed3-C6The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring
Base, L1-C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4 C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 member are miscellaneous
Ring group, C3-C11Naphthenic base and C4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces,
The group is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN,
NO2, F, Cl, Br and I；Wherein L1It is not present, or is selected from the group, which is made up of: C1-C6Alkylidene, C2-C6Alkenylene,
C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene and C2-C6Alkynylene, it is single
Solely or as group a part, be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、
SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, the 4- condensed with phenyl group
6 unit monocycle heterocycles, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5 C6-C10First aryl, 5-11 unit's heteroaryl, with
The condensed 4-6 unit monocycle heterocycle of phenyl group, C3-C11Naphthenic base and C4-C11Cycloalkenyl is optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and
I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6 C1-C6Alkyl, C2-C6Alkenyl,
And C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、
OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Ring
Alkyl, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、
F, Cl, Br and I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R9 C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23、OH、
Oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Ring
The substituent group that alkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl, with
And 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN,
NO2, F, Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
Heterocycle；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
The substituent group that heterocycle is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl,
C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and
I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15 C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I:
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
Another aspect of the present invention relates to the pharmaceutical compositions comprising the compound of the present invention and pharmaceutical carrier.It can be according to this
The method of invention gives this kind of composition usually as a part of therapeutic scheme, for treating or preventing and capsule fiber
Change the relevant illness of transmembrane conductance regulator activity and obstacle.In a specific aspect, pharmaceutical composition can additionally comprise
It is suitble to the other treatment active constituent being applied in combination with the compound of the present invention.It is described other at a more specific aspect
Therapeutic activity ingredient is the medicament for treating cystic fibrosis.
In addition, can be used in pharmaceutical composition and treatment method described herein in the compound of the present invention preparation with
And using when be pharmaceutically acceptable.
Another aspect of the present invention is related to adjusting for treating or preventing in mammal with CF transmembrane conductance
The method of protein active relevant illness and obstacle.More specifically, this method can be used to treat or prevent and cystic fibrosis, dry
Dry syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease or the related illness of chronic obstructive airway disease and obstacle.Therefore,
The compound of the present invention and composition can be used as treating or preventing the disease of cystic fibrosis transmembrane conductance regulator adjusting
Drug.
Compound described further herein, the composition comprising these compounds, the method for preparing these compounds, with
And the method by giving these compounds treatment or prevention illness and obstacle.
In a specific aspect, the compound of the present invention is provided for using in treatment cystic fibrosis.One
A specific aspect provides the compound of the present invention for treating as caused by the mutation of I, II, III, IV, V and/or VI class
It is used in cystic fibrosis.
The present invention also provides the medicines of the Suitable pharmaceutical carriers comprising the compound of the present invention and for using in medicine
Compositions.In a specific aspect, which is used in treatment cystic fibrosis use.
Following paragraphs describe object of the present invention and other purposes.It is not considered that these purposes reduce it is of the invention
Range.
Specific embodiment
This document describes the compound with formula (I),
Wherein R1、R2、R2A、R3、R3A、R4、R4AAnd R5It is as determined in the above summary of the invention and following specific embodiments
Justice.In addition, further including the composition containing this kind of compound and treating illness and barrier using this kind of compound and composition
The method hindered.
The compound for including herein can contain there is more than one one in any substituent group or in the formula of this paper
A or multiple variables.The definition when definition for occurring variations per hour every time occurs independently of another time.In addition, only when the group of substituent group
It closes and just allows such combination when generating stable compound.Stable compound is the chemical combination that can be separated from reaction mixture
Object.
Definition
Note that as used in this specification and expected claim, it is unless the context clearly indicates otherwise, no
Then singular " one/one (a/an) " and " being somebody's turn to do (the) " include plural referents.Thus, for example, referring to that " compound " wraps
Single compound is included together with one or more identical or different compounds；It is single to refer to that " pharmaceutically acceptable carrier " means
Pharmaceutically acceptable carrier together with one or more pharmaceutically acceptable carriers etc..
As used in this specification and appended claim, following term has shown meaning, unless regulation
In contrast:
Term " alkenyl " as used herein means containing from 2 to 10 carbon and containing the straight of at least one carbon-to-carbon double bond
Chain or branch hydrocarbon chain.Term " C2-C6Alkenyl " means the alkenyl containing 2-6 carbon atom.C2-C6The non-limiting example of alkenyl
Including butyl- 1,3- dialkylene, vinyl, 2- acrylic, 2- methyl -2- acrylic, 3- cyclobutenyl, 4- pentenyl and 5- hexene
Base.
Term " C as used herein1-C6Alkoxy " refer to by oxygen atom connect with parent molecular moiety as herein
Defined C1-C6Alkyl group.The non-limiting example of alkoxy includes methoxyl group, ethyoxyl, propoxyl group, 2- propoxyl group, fourth
Oxygroup, tert-butoxy, amoxy and hexyloxy.
Term " alkyl " as used herein means the linear chain or branched chain hydrocarbon chain radical of saturation.In some cases, alkyl
Carbon atom number in part is by prefix " Cx-Cy" indicate, wherein x is the minimum value of carbon atom in substituent group, and y is maximum value.Cause
This, for example, " C1-C6Alkyl " means alkyl substituent and " C containing from 1 to 6 carbon atom1-C3Alkyl " mean containing from
The alkyl substituent of 1 to 3 carbon atom.The representative example of alkyl include but is not limited to methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, sec-butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1- methyl butyl, 2- methyl fourth
Base, 3- methyl butyl, 3,3- dimethylbutyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1-
Methyl-propyl, 2- methyl-propyl, 1- ethyl propyl and 1,2,2- thmethylpropyls.Unless otherwise specified, art used herein
Language " alkyl ", " C1-C6Alkyl ", " C1-C4Alkyl " and " C1-C3Alkyl " is unsubstituted.
Term " alkylidene (alkylene or alkylenyl) " means the bilvalent radical derived from linear chain or branched chain saturated hydrocarbon chain
Group, such as with 1 to 10 carbon atom or 1 to 6 carbon atom (C1-C6Alkylidene) or with 1 to 4 carbon atom or have 1 to
3 carbon atom (C1-C3Alkylidene) or with 2 to 6 carbon atom (C2-C6Alkylidene).C1-C6The example of alkylidene includes but not
It is limited to-CH2-、-CH2CH2-、-C(CH3)2-CH2CH2CH2-、-C(CH3)2-CH2CH2-、-CH2CH2CH2CH2And-CH2CH
(CH3)CH2-。
Term " alkenylene " as used herein means derived from linear chain or branched chain hydrocarbon, double containing at least one carbon-to-carbon
The bivalent group of key.Term " C as used herein2-C6Alkenylene " mean it is derived from linear chain or branched chain hydrocarbon, containing from 2 to 6
A carbon and bivalent group containing at least one carbon-to-carbon double bond.
Term " alkynylene " as used herein mean it is derived from linear chain or branched chain hydrocarbyl group, contain at least one carbon-
The bivalent group of three key of carbon.Term " C as used herein2-C6Alkynylene " mean derived from linear chain or branched chain hydrocarbyl group, contain
There are from 2 to 6 carbon atoms and the bivalent group containing at least one carbon-carbon triple bond.
Term " C as used herein2-C6Alkynyl " means containing from 2 to 6 carbon atoms and contains at least one carbon-to-carbon three
The linear chain or branched chain hydrocarbyl group of key.C2-C6The representative example of alkynyl includes but is not limited to acetenyl, 1- propinyl, 2- propine
Base, 3- butynyl, valerylene base and 1- butynyl.
Term " C as used herein3-C11Naphthenic base " means double containing 3-11 carbon atom, zero heteroatoms and zero
The hydrocarbon ring group of key.C3-C11Group of naphthene base can be single ring (monocycle) or have two or more ring (polycyclic or two rings
).Monocyclic cycloalkyl group usually contains from 3 to 8 carboatomic ring atom (C3-C8Monocyclic cycloalkyl), and even more usually contain
3 to 6 carboatomic ring atom (C3-C6Monocyclic cycloalkyl).The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, hexamethylene
Base, suberyl and cyclooctyl.Polycyclic naphthene base group contains two or more rings, and bicyclic cycloalkyl is containing there are two rings.
In certain embodiments, polycyclic naphthene base group contains 2 or 3 rings.Ring in polycyclic and bicyclic cycloalkyl group can be bridge
Even, condensed or screw orientation, or combinations thereof.In loop coil naphthenic base, an atom is common to two different rings.Loop coil
The example of naphthenic base includes spiral shell [2.5] octyl and spiral shell [4.5] decyl.In bridging naphthenic base, ring shared at least two is not
Adjacent atom.The example of bridging naphthenic base includes but is not limited to two rings [1.1.1] pentyl, two rings [2.2.2] octyl, two rings
[3.2.1] octyl, two rings [3.1.1] heptyl, two rings [2.2.1] heptyl, two rings [3.2.2] nonyl, two rings [3.3.1] nonyl,
With two rings [4.2.1] nonyl, tricyclic [3.3.1.03,7] nonyl (octahydro -2,5- first bridge pentalene base or positive adamantyl),
Tricyclic [3.3.1.13,7] decyl (adamantyl) and tricyclic [4.3.1.13,8] undecyl (full adamantyl
(homoadamantyl)).In condensed ring naphthenic base, ring shares a common key.The example of condensed ring naphthenic base includes but unlimited
In naphthalane (decahydro naphthalene), two rings [3.1.0] hexyl, He Erhuan [2.2.0] octyl.
Term " C as used herein3-C6Naphthenic base " means containing 3-6 carbon atom, zero heteroatoms and zero double bond
Hydrocarbon ring group.C3-C6Group of naphthene base can be there are two single ring (monocycle) or tools ring (two rings).
Term " C as used herein4-C11Cycloalkenyl " mean containing 4-11 carbon atom, zero heteroatoms and one or
The non-aromatic hydrocarbon ring group of multiple double bonds.C4-C11Cycloalkenyl groups can be single ring (monocycle) or have two or more
A ring (polycyclic or two rings).The example of monocyclic cycloalkenyl include cyclobutane base, cyclopentenyl, cyclohexenyl group, cyclohexadienyl,
Suberyl, cyclo-octene base and cyclo-octadiene base.The example of bicyclic cycloalkenyl includes two rings [2.2.1] hept-2-ene" base.
Term " C as used herein4-C8Monocyclic cycloalkenyl " means cyclobutane base, cyclopentenyl, cyclohexenyl group, hexamethylene two
Alkenyl, suberyl, cycloheptadiene base, cyclo-octene base and cyclo-octadiene base.
Term " C as used herein4-C7Monocyclic cycloalkenyl " means cyclobutane base, cyclopentenyl, cyclohexenyl group, hexamethylene two
Alkenyl and suberyl.
Term " halogenated " or " halogen " as used herein mean Cl, Br, I and F.
Term " halogenated alkyl " as used herein means alkyl group as herein defined, one of them, two, three
It is a, four, five or six hydrogen atoms are replaced by halogen.Term " C1-C6Halogenated alkyl " means C as herein defined1-C6
Alkyl group, one of them, two, three, four, five or six hydrogen atoms are replaced by halogen.Term " C1-C3Alkyl halide
Base " means C as herein defined1-C3Alkyl group, one of them, two, three, four or five hydrogen atoms are by halogen generation
It replaces.The representative example of halogenated alkyl includes but is not limited to chloromethyl, 2- fluoro ethyl, 2,2- bis-fluoro ethyls, methyl fluoride, 2,2,2-
The chloro- 3- fluorine amyl group of trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl group, 2-, triRuorobutyl and trifluoro propyl.
Term " halogenated alkoxy " as used herein means alkoxy base as herein defined, one of them, two
It is a, three, four, five or six hydrogen atoms are replaced by halogen.Term " C1-C6Halogenated alkoxy " means as defined herein
C1-C6Alkyl group, one of them, two, three, four, five or six hydrogen atoms are replaced by halogen.
Term " 4-12 circle heterocyclic ring " as used herein means the hydrocarbon ring group of 4-12 carboatomic ring atom, wherein at least one
One or more hetero atoms that carbon atom is independently selected from the following group replace, which is made up of: O, N and S.The 4-12 member is miscellaneous
Ring can be single ring (monocycle) or have two or more rings (two rings or polycyclic).In certain embodiments, the monocycle
Heterocycle is quaternary, five yuan, hexa-atomic, seven yuan or eight membered hydrocarbon rings, and wherein at least one carboatomic ring atom is independently selected from the one of the following group
A or multiple hetero atoms replace, which is made up of: O, N and S.In certain embodiments, which is 4-7 member hydrocarbon
Ring, wherein at least one carboatomic ring atom are replaced by one or more hetero atoms.Quaternary monocyclic heterocycles contain zero or one double bond,
And a hetero atom selected from the group below, the group are made up of: O, N and S.Five unit monocycle heterocycles contain zero or one double bond
With one, two or three hetero atom selected from the group below, which is made up of: O, N and S.The example packet of five unit monocycle heterocycles
It includes in ring containing those of following item: 1 O；1 S；1 N；2 N；3 N；1 S and 1 N；1 S and 2 N；1 O
With 1 N；Or 1 O and 2 N.The non-limiting example of 5 membered monocyclic ring heterocyclic group includes 1,3-dioxolane base, tetrahydrofuran
Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, imidazolidinyl, oxazolidinyl, imidazolinyl, imidazolidinyl, different evil
Oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, thiazolinyl and thiazolidinyl.
Single six-membered rings heterocycle contains zero, one or two double bonds and one, two or three hetero atom selected from the group below, the group by
Consisting of: O, N and S.The example of single six-membered rings heterocycle is included in ring containing those of following item: 1 O；2 O；1 S；2
A S；1 N；2 N；3 N；1 S, 1 O and 1 N；1 S and 1 N；1 S and 2 N；1 S and 1 O；1 S and 2
O；1 O and 1 N；And 1 O and 2 N.The example of single six-membered rings heterocycle includes dihydro pyranyl, Isosorbide-5-Nitrae-dioxanes base, 1,
3- dioxanes base, Isosorbide-5-Nitrae-dithianyl, hexahydropyrimidine, morpholinyl, Isosorbide-5-Nitrae-dihydropyridine base, piperazinyl, piperidyl, oxinane
Base, 1,2,3,6- tetrahydro pyridyls, tetrahydro thiapyran base, thio-morpholinyl, thiophene oxane base and trithiane base.Seven yuan and eight unit monocycles
Heterocycle contains zero, one, two or three double bonds and one, two or three hetero atom selected from the group below, the group by with
Lower composition: O, N and S.The example of monocyclic heterocycles include but is not limited to azetidinyl, nitrogen heterocyclic heptyl, aziridinyl,
Isosorbide-5-Nitrae-Diazesuberane base, dihydro pyranyl, 1,3- dioxanes base, 1,3-dioxolane base, 1,3- dithiolane base, 1,3-
Dithianyl, imidazolinyl, imidazolidinyl, isothiazoline base, isothiazole alkyl, isoxazoline base, isoxazolidinyl, morpholine
Base, oxazepine cycloheptyl alkyl, oxadiazoline base, oxadiazoles alkyl, oxazoline group, oxazolidinyl, oxetanyl, piperazine
Base, piperidyl, pyranose, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuran base, tetrahydro pyridyl, four
Hydrogen pyranose, tetrahydro-thienyl, Thiadiazoline base, thiadiazoles alkyl, thiazolinyl, thiazolidinyl, thio-morpholinyl, thio pyrrole
It mutters base and trithiane base.Polycyclic heterocyclic group contains two or more rings, and bicyclic heterocycles are containing there are two rings.Certain
In embodiment, polycyclic heterocyclic group contains 2 or 3 rings.Ring in polycyclic and bicyclic heterocyclic moieties can be bridging, condensed or spiral shell
Rotation orientation, or combinations thereof.In Spirocyclic heterocyclic, an atom is common to two different rings.Spirocyclic heterocyclic it is unrestricted
Property example includes 6- oxaspiro [2.5] octyl, 2- azaspiro [3.3] heptyl, 5- azaspiro [2.4] heptyl, 5- azaspiro
[2.5] octyl, 2- azaspiro [3.5] nonyl, 2- azaspiro [3.4] octyl, 3- azaspiro [5.5] undecyl, 5- azaspiro
[3.4] octyl, 2- oxaspiro [3.3] heptyl, 2- oxa- -6- azaspiro [3.3] heptyl, 6- oxa- -2- azaspiro [3.4] are pungent
Base, 6- azaspiro [3.4] octyl, 7- azaspiro [3.5] nonyl, 8- azaspiro [4.5] decyl, 1- oxa- -7- azaspiro [4.4]
Nonyl, 1- oxa- -7- azaspiro [3.5] nonyl, 1- oxa- -8- azaspiro [4.5] decyl, 1- oxa- -3,8- diaza spiro
[4.5] decyl, 1- oxa- -4,9- diaza spiro [5.5] undecyl, 2- oxa- -7- azaspiro [3.5] nonyl, 5- oxa- -2-
Azaspiro [3.5] nonyl, 6- oxa- -2- azaspiro [3.5] nonyl, 7- oxa- -2- azaspiro [3.5] nonyl, 8- oxa- -2- nitrogen
Miscellaneous spiral shell [4.5] decyl, 2,7- diaza spiro [4.4] nonyl, Isosorbide-5-Nitrae-dioxa -8- azaspiro [4.5] decyl, 1,3,8- tri- azepines
Spiral shell [4.5] decyl.In fused ring heterocycle, ring shares a common key.The example of fused bicyclic heterocycle is thick with phenyl group
The 4-6 unit monocycle heterocycle or and C of conjunction3-C6Monocyclic cycloalkyl condensed 4-6 unit monocycle heterocycle or and C4-C7Monocyclic cycloalkenyl is thick
The 4-6 unit monocycle heterocycle of conjunction or the 4-6 unit monocycle heterocycle heterocyclic fused with 4-7 unit monocycle.The example of fused bicyclic heterocycle includes
But be not limited to 1,2- dihydro phthalazinyl, 3,4- dihydro -2H- benzo [b] [Isosorbide-5-Nitrae] benzodioxepin base, chromanyl,
Chromene base, isochroman base, 2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin base, iso-dihydro-indole-group, 2,3- dihydrobenzene
And [b] thienyl, hexahydro -1H- ring penta [c] furyl, 3- oxabicyclo [3.1.0] hexyl, 3- azabicyclic [3.1.0] oneself
Base, benzopyranyl, benzo thiopyranyl, indolinyl, decahydro pyrrolo- [3,4-b] azepineBase, 2,3- dihydrobenzene
And furyl, 2,3- dihydrobenzo thienyl, 2,3- dihydro -1H- indyl, 3,4- dihydro-isoquinoline -2 (1H)-base, 2,3,4,
6- tetrahydro -1H- pyrido [1,2-a] pyrazine -2- base, hexahydro pyrans simultaneously [3,4-b] [Isosorbide-5-Nitrae] oxazines -1 (5H)-base, hexahydropyrrolo
And [3,4-c] pyrroles -2 (1H)-base, [c] pyrroles -3a of hexahydro ring penta (1H)-base, hexahydro -1H- oxazole simultaneously [3,4-a] pyrazinyl,
Octahydro pyrrolo- [3,4-b] [Isosorbide-5-Nitrae] oxazines base, octahydro imidazo [1,5-a] pyrazinyl, octahydro pyrrolo- [1,2-a] pyrazinyl,
Octahydro -1H- pyrrolo- [3,2-c] pyridyl group and octahydro pyrrolo- [3,4-c] pyrrole radicals.In bridged heterocyclic, ring is shared at least
Two non-conterminous atoms.The example of this bridged heterocyclic includes but is not limited to 8- oxabicyclo [3.2.1] octyl, 7- oxa-
Two rings [2.2.1] heptane base, azabicyclic [2.2.1] heptyl (including 2- azabicyclic [2.2.1] hept- 2- yl), 8- azepine two
Ring [3.2.1] octyl- 8- base, octahydro -2,5- epoxy pentalene, 8- oxa- -3- azabicyclic [3.2.1] octyl, hexahydro -
1H-1,4- first bridged ring penta [c] furans, azepine-adamantane (1- aza-tricycle [3.3.1.1-3,7] decane) and oxa--Buddha's warrior attendant
Alkane (2- oxatricyclo [3.3.1.13,7] decane).Miscellaneous nuclear nitrogen and sulfur heteroatom can optionally be oxidized (such as 1,1- bis-
Oxidation tetrahydro-thienyl, 1,1- titanium dioxide -1,2- thiazolidinyl, 1,1- titanium dioxide thio-morpholinyl) and nitrogen-atoms can appoint
Selection of land is quaternized.The non-limiting example of polycyclic heterocycle include 6,7- dihydro-[1,3] dioxole simultaneously [4,5-f]
Benzofuranyl.
Term " 4-6 circle heterocyclic ring " as used herein means the hydrocarbon ring group of 4-6 carboatomic ring atom, wherein at least one carbon
One or more hetero atoms that atom is independently selected from the following group replace, which is made up of: O, N and S.Quaternary monocyclic heterocycles
It is made up of containing zero or one double bond and a hetero atom selected from the group below, the group: O, N and S.Five unit monocycles are miscellaneous
Ring contains zero or one double bond and one, two or three hetero atom selected from the group below, which is made up of: O, N and S.
The example of five unit monocycle heterocycles is included in ring containing those of following item: 1 O；1 S；1 N；2 N；3 N；1 S and 1
A N；1 S and 2 N；1 O and 1 N；Or 1 O and 2 N.The non-limiting example of 5 membered monocyclic ring heterocyclic group includes 1,3-
Dioxolanyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, imidazolidinyl, oxazolidinyl, imidazoles
Quinoline base, imidazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, thiophene
Oxazoline base and thiazolidinyl.Single six-membered rings heterocycle contains zero, one or two double bonds and one, two or three and is selected from down
The hetero atom of group, the group are made up of: O, N and S.The example of single six-membered rings heterocycle includes that for containing following item in ring
It is a little: 1 O；2 O；1 S；2 S；1 N；2 N；3 N；1 S, 1 O and 1 N；1 S and 1 N；1 S and 2 N；1
A S and 1 O；1 S and 2 O；1 O and 1 N；And 1 O and 2 N.The example of single six-membered rings heterocycle includes dihydropyran
Base, Isosorbide-5-Nitrae-dioxanes base, 1,3- dioxanes base, Isosorbide-5-Nitrae-dithianyl, hexahydropyrimidine, morpholinyl, Isosorbide-5-Nitrae-dihydropyridine base, piperazine
Base, piperidyl, THP trtrahydropyranyl, 1,2,3,6- tetrahydro pyridyls, tetrahydro thiapyran base, thio-morpholinyl, thiophene oxane base and three thiophenes
Alkyl.
Term " 5-11 unit's heteroaryl " as used herein means bicyclic heteroaryl and bicyclic heteroaryl." 5-7 member heteroaryl
Base " is five yuan or hexatomic ring.Five-membered ring is containing there are two double bonds.Five-membered ring can contain a hetero atom selected from O or S；Or one
A, two, three or four nitrogen-atoms and optional an oxygen or a sulphur atom.Hexatomic ring contain there are three double bond and one,
Two, three or four nitrogen-atoms.The example of 5-6 unit monocycle heteroaryl includes but is not limited to furyl, imidazole radicals, isoxazole
Base, isothiazolyl, oxadiazoles base, 1,3-oxazoles base, pyridazine ketone group, pyriconyl, pyridyl group, pyridazinyl, pyrimidine radicals, pyrazine
Base, pyrazolyl, pyrrole radicals, tetrazole radical, thiadiazolyl group, 1,3-thiazoles base, thienyl, triazolyl and triazine radical.Bicyclic heteroaryl
It is made up of: the bicyclic heteroaryl or and C condensed with phenyl3-C6Monocyclic cycloalkyl condensed bicyclic heteroaryl or and C4-
C7The condensed bicyclic heteroaryl of monocyclic cycloalkenyl or the bicyclic heteroaryl condensed with bicyclic heteroaryl or with 4-7 unit monocycle heterocycle
Condensed bicyclic heteroaryl.The representative example of bicyclic heteroaryl group includes but is not limited to 4H- furans simultaneously [3,2-b] pyrroles
Base, benzofuranyl, benzothienyl, benzo isoxazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazole base, phthalazines
Base, 2,6- pyrrolin simultaneously [3,4-c] pyrazoles -5 (4H)-base, 6,7- dihydro-pyrazol simultaneously [1,5-a] pyrazine -5 (4H)-base, 6,
7- dihydro -1,3- benzothiazolyl, imidazo [1,2-a] pyridyl group, indazolyl, indyl, isoindolyl, isoquinolyl, naphthalene
Piperidinyl, pyridine-imidazole base, quinolyl, 4,5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridyl group, 2,4,6,7- tetrahydro -5H- pyrazoles
And [4,3-c] pyridine -5- base, thiazole simultaneously [5,4-b] pyridine -2- base, thiazole simultaneously [5,4-d] pyrimidine -2-base and 5,6,7,8- tetra-
Hydrogen quinoline -5- base.Heteroaryl ring nitrogen is optionally oxidized or is optionally partially alkylated or alkylated.
Term " 6-10 member aryl " as used herein means to contain 6-10 carbon atom, zero heteroatoms and one or more
The hydrocarbon ring group of a aromatic ring.The 6-10 member aryl group can be there are two single ring (monocycle) or tools ring (two rings).Two rings
Aryl is naphthalene or the phenyl condensed with monocyclic cycloalkyl or the phenyl condensed with monocyclic cycloalkenyl.The representative of 6-10 member aryl
Property example includes but is not limited to phenyl, indenyl, tetralyl, dihydro indenyl (indanyl), naphthalene etc..
Unless otherwise stated, aryl, naphthenic base, cycloalkenyl, heterocycle and heteroaryl including exemplary loop are optional
Ground is substituted；And any substitutive atom by including in loop system is connect with parent molecular moiety.
Term " hetero atom " as used herein means nitrogen, oxygen and sulphur.
Term " oxo " as used herein means=O group.
Term " radioactive label " means the compound of the present invention, and wherein at least one atom is radioactive atom or radiation
Property isotope, wherein the radioactive atom or isotope spontaneously emit gamma-rays or high energy particle (such as α particle or β particle)
Or positive electron.The example of this radioactive atom includes but is not limited to3H (tritium),14C、11C、15O、18F、35S、123I, and125I。
When non-hydrogen group replaces any hydrogen-based that may replace atom of a part, which is described as " being substituted
".Thus, for example, the heterocyclic moiety being substituted is the heterocycle for the hydrogen group that the non-hydrogen group of wherein at least one replaces on heterocycle
Part.It should be understood that each non-hydrogen group may be the same or different (unless another if there is one or more substitutions in certain a part
It is described).
If a part is described as " being optionally substituted ", the part can be (1) it is unsubstituted, or (2)
It is substituted.If a part is described as optionally being replaced by most particular number of non-hydrogen group, which be can be
(1) unsubstituted；Or (2) replaced by the at most particular number of non-hydrogen group or be substituted at most on the part can
The maximum number of the position of substitution, takes smaller value.Thus, for example, if a part is described as optionally by most 3 non-hydrogen
The heteroaryl that group replaces, then any heteroaryl that may replace position having less than 3 will optionally by most only with it is miscellaneous
Aryl, which has, may replace the non-hydrogen group substitution of position as many.For illustrating, (only there is tetrazole radical one desirable to be subrogated for it
Set) will optionally it be replaced by an at most non-hydrogen group.For further illustrating, if ammonia nitrogen is described as optionally by extremely
More 2 non-hydrogen groups replace, then primary amino group nitrogen will optionally be replaced by most 2 non-hydrogen groups, and secondary amino nitrogen will be optionally low
By at most only 1 non-hydrogen group replaces.
Term " treatment (treat, treating and treatment) " refer to alleviation or eliminate disease and/or its with disease
The method of shape.In certain embodiments, " treatment (treat, treating and treatment) " refers at least one possibility of improvement
The body parameter not distinguished by subject.In another embodiment, " treatment (treat, treating and treatment) "
Refer to and adjusts disease or obstacle (such as stable symptom experienced), adjusting disease or barrier in terms of physiology in physics aspect
(such as stable physical parameter) or both is hindered all to have.In another embodiment, " treatment (treat, treating and
Treatment) " refer to the progress for slowing down disease or obstacle.
Term " prevention " (" prevent ", " preventing " and " prevention ") refers to prevention disease and/or its companion
With paresthesia epilepsy or make method of the subject from obtaining disease.As it is used herein, " prevention (prevent,
Preventing and prevention) " it further include postponing the breaking-out of disease and/or its simultaneous phenomenon and reducing subject's acquisition
Or the risk of disease or obstacle occurs.
Phrase " therapeutically effective amount " means a certain amount of compound or its pharmaceutically acceptable salt, when individually or with it is another
One therapeutic agent is combined to when giving for treating specific subject or subject group, which is enough to prevent quilt to a certain extent
The development of one or more symptoms of the illness or obstacle for the treatment of is mitigated." therapeutically effective amount " can be according to compound, disease
Disease and its seriousness and change situations such as age, the weight, health of subject to be treated.For example, the mankind or other
In mammal, therapeutically effective amount can be determined empirically in laboratory or clinical setting, or can be for according to U.S.'s food
The directive/guide institute of drug administration (United States Food and Drug Administration) or same foreign organization
Amount needed for the disease specific for the treatment of and subject.
Term " subject " is defined herein as referring to that animal, such as mammal, including but not limited to primate are dynamic
Object (for example, people), ox, sheep, goat, pig, horse, dog, cat, rabbit, rat, mouse etc..In one embodiment, subject is
People.Term " mankind ", " patient " and " subject " is used interchangeably herein.
Term " one or more " refers to one to eight.In one embodiment, it refers to one to eight.Implement at one
In example, it refers to one to seven.In one embodiment, it refers to one to six.In one embodiment, it refers to one to five
It is a.In one embodiment, it refers to one to four.In one embodiment, it refers to one or three.In another embodiment
In, it refers to one to three.In another embodiment, it refers to one or two.In yet another embodiment, it refers to two
It is a.In another other embodiment, it refers to one.
Term " bioisostere " as used herein means there is substantially similar part physically or chemically,
It assigns biological property as the compounds with formula (I).The example of-C (O) OH bioisostere includes-P (O)
(OH)2、-P(O)(OH)(H)、-P(O)(OH)(O-C1-C6Alkyl) ,-P (O) (CH3)(OH)、-B(OH)2、-SO3H、-CH(OH)
CF3、-C(O)NH(OH)、-C(O)NH(CN)、-C(O)NHSO2RG3a、-SO2NHC(O)RG3a、-C(O)NHSO2NHRG3a、-C(O)
NHSO2N(RG3a)2、-SO2NH2、-SO2NHRG3a、-SO2N(RG3a)2、-C(O)NHS(O)(RG3a)=NC (O) RG3a、-C(O)NHS
(O)(RG3a)=NRG3b、 Wherein
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl, C1-C6Halogenated alkyl or
GA；
RG3bIt is hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl or GA；
GAIt is independently naphthenic base, cycloalkenyl, aryl or heteroaryl at each occurrence, is not take each independently
Generation or by 1,2 or 3 R being selected independentlyuWhat group replaced；Wherein
RuIt is independently C at each occurrence1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halogen, C1-C6Halogenated alkyl ,-
CN, oxo ,-NO2、-ORj、-OC(O)Rk、-OC(O)N(Rj)2、-S(O)2Rj、-S(O)2N(Rj)2、-C(O)Rk、-C(O)ORj、-C
(O)N(Rj)2、-N(Rj)2、-N(Rj)C(O)Rk、-N(Rj)S(O)2Rk、-N(Rj)C(O)O(Rk) or-N (Rj)C(O)N(Rj)2；
RjAt each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl or C1-C6Alkyl halide
Base；And
RkAt each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl or C1-C6Halogenated alkyl.
As used herein, " one or more I class mutation " refers to the mutation of interferencing protein synthesis.They cause
Translation is introduced in mRNA shifts to an earlier date termination signal (terminator codon).Truncated CFTR protein is unstable and drops rapidly
Solution, so net effect is that do not have protein on the film of top.Specifically, one or more I class mutation refer to p.Gly542X
(G542X), W1282X, c.489+1G > T (621+1G > T) or c.579+1G > T (711+1G > T) mutation.More specifically,
One or more I class mutation refer to G542X；Or W1282X mutation.
As used herein, " one or more II class mutation " refers to the mutation for influencing protein maturation.This causes cannot
Correctly folded and/or transported the generation to the CFTR protein in its site functioned on the film of top.Specifically, one
Kind or the mutation of a variety of II classes refer to Phe508del (F508del), Ile507del or Asn1303Lys (N1303K) mutation.More
Specifically, one or more II class mutation refer to F508del or N1303K mutation.
As used herein, " one or more Group III mutation " refers to the mutation for changing the adjusting in the channel CFTR.Mutation
CFTR albumen suitably transported and be positioned at plasma membrane but cannot be activated or it cannot function as chloride channel play make
With.Specifically, the mutation of one or more Group IIIs refer to p.Gly551Asp (G551D), G551S, R553G, G1349D,
S1251N, G178R, S549N mutation.More specifically, the mutation of one or more Group IIIs refer to G551D, R553G, G1349D,
S1251N, G178R or S549N mutation.
As used herein, " one or more IV class mutation " refers to the mutation for influencing chloride conductance.CFTR albumen quilt
Cell membrane is correctly transported, but generating reduced chlorination logistics or " gating deficit " (is located in transmembrane domain
Missense mutation).Specifically, the mutation of one or more IV classes refer to p.Arg117His (R117H), R347P or
P.Arg334Trp (R334W) mutation.
As used herein, " one or more V class mutation " refers to the water for reducing the CFTR of proper function at the film of top
Mutation (such as the mutation of part aberrant splicing or inefficient transport missense mutation) that is flat or leading to " conduction defect ".Specifically, one
Kind or a variety of V classes mutation refer to c.1210-12T [5] (5T allele), c.S3140-26A > G (3272-26A > G),
C.3850-2477C > T (3849+10kbC > T) is mutated.
As used herein, " one or more VI class mutation " refers to mutation or the shadow for the stability for reducing existing CFTR
It rings the adjusting in other channels and then leads to the mutation of CFTR albumen inherent instability.In fact, although there is function, CFTR
Albumen is unstable in cell surface, and it is removed and degraded rapidly by cellular machineries.Specifically, one or more VI classes are prominent
Become F508del, 120del23, N287Y, 4326dellTC or 4279insA mutation for referring to rescue.More specifically, it is a kind of or
A variety of VI class mutation refer to the F508del mutation of rescue.
Compound
The compound of the present invention has logical formula (I) as described above.
The occurrence of variable groups is as described below.If appropriate, this kind of value can with hereinbefore or hereinafter defined in other values, fixed
Any one of justice, claim or embodiment are used together.
Formula (I)
One embodiment is related to the compound with (I),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl and C3-C6Naphthenic base；
R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl；Its
In the R3 C1-C6The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of:
C1-C6Alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3 C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl
The substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkane
Oxygroup, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And
R3AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R3And R3AC is formed together with the carbon attached by them3-C+Naphthenic base；Wherein by R3And R3AAnd attached by them
The C that carbon is formed3-C6The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring
Base, L1-C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4 C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 member are miscellaneous
Ring group, C3-C11Naphthenic base and C4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces,
The group is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN,
NO2, F, Cl, Br and I；Wherein L1It is not present, or is selected from the group, which is made up of: C1-C6Alkylidene, C2-C6Alkenylene,
C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene and C2-C6Alkynylene, it is single
Solely or as group a part, be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、
SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, the 4- condensed with phenyl group
6 unit monocycle heterocycles, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5 C6-C10First aryl, 5-11 unit's heteroaryl, with
The condensed 4-6 unit monocycle heterocycle of phenyl group, C3-C11Naphthenic base and C4-C11Cycloalkenyl is optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and
I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6 C1-C6Alkyl, C2-C6Alkenyl,
And C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、
OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Ring
Alkyl, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、
F, Cl, Br and I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R9 C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23、OH、
Oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Ring
The substituent group that alkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl, with
And 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN,
NO2, F, Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
Heterocycle；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
The substituent group that heterocycle is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl,
C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and
I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15 C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18 C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21 C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I；
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
Another embodiment is related to the compound with formula (I),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl and C3-C6Naphthenic base；
R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl；Its
In the R3 C1-C6The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of:
C1-C6Alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3 C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl
The substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkane
Oxygroup, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And
R3AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；Wherein by R3And R3AAnd attached by them
The C that carbon is formed3-C6The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6Alkylidene)x-5-11
Unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-C11Naphthenic base and (C1-C6Alkylene
Base)x-C4-C11Cycloalkenyl；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)x-
The 5-11 unit's heteroaryl of 5-11 unit's heteroaryl, (C1-C6Alkylidene)x4-12 circle heterocyclic ring the base, (C of -4-12 circle heterocyclic ring base1-C6Alkylene
Base)x-C3-C11The C of naphthenic base3-C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11The C of cycloalkenyl4-C11Cycloalkenyl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、C(O)
NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and C4-
C11Cycloalkenyl；The wherein R5 C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and C4-C11Cycloalkenyl is optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14, OH, oxo,
CN、NO2, F, Cl, Br and I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6 C1-C6Alkyl, C2-C6Alkenyl,
And C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、
OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Ring
Alkyl, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、
F, Cl, Br and I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R9 C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23、OH、
Oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Ring
The substituent group that alkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl, with
And 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN,
NO2, F, Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
Heterocycle；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
The substituent group that heterocycle is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl,
C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15 C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18 C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21 C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I；
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl；And
X is 0 or 1.
In one embodiment of formula (I), R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6, with
And C (O) NR7R8.In another embodiment of formula (I), R1It is C (O) R6Or C (O) OR6.In another embodiment of formula (I)
In, R1It is SO2R6.In another embodiment of formula (I), R1It is C (O) R6.In another embodiment of formula (I), R1It is C
(O)OR6.In another embodiment of formula (I), R1It is C (O) NR7R8。
In one embodiment of formula (I), R2It is C (O) OH or its bioisostere.In another reality of formula (I)
It applies in example, R2It is-P (O) (OH)2、-P(O)(OH)(H)、-P(O)(OH)(O-C1-C6Alkyl) ,-P (O) (CH3)(OH)、-B
(OH)2、-SO3H、-CH(OH)CF3、-C(O)NH(OH)、-C(O)NH(CN)、-C(O)NHSO2RG3a、-SO2NHC(O)RG3a、-C
(O)NHSO2NHRG3a、-C(O)NHSO2N(RG3a)2、-SO2NH2、-SO2NHRG3a、-SO2N(RG3a)2、-C(O)NHS(O)(RG3a)=
NC(O)RG3a、-C(O)NHS(O)(RG3a)=NRG3b、 Wherein
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl, C1-C6Halogenated alkyl or
GA；
RG3bIt is hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl or GA；
GAIt is independently naphthenic base, cycloalkenyl, aryl or heteroaryl at each occurrence, is not take each independently
Generation or by 1,2 or 3 R being selected independentlyuWhat group replaced；Wherein
RuIt is independently C at each occurrence1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halogen, C1-C6Halogenated alkyl ,-
CN, oxo ,-NO2、-ORj、-OC(O)Rk、-OC(O)N(Rj)2、-S(O)2Rj、-S(O)2N(Rj)2、-C(O)Rk、-C(O)ORj、-C
(O)N(Rj)2、-N(Rj)2、-N(Rj)C(O)Rk、-N(Rj)S(O)2Rk、-N(Rj)C(O)O(Rk) or-N (Rj)C(O)N(Rj)2；
RjAt each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl or C1-C6Alkyl halide
Base；And
RkAt each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl or C1-C6Halogenated alkyla?
In another embodiment of formula (I), R2It is-P (O) (OH)2、-P(O)(OH)(H)、-B(OH)2、-SO3H、-CH(OH)CF3、-C
(O)NH(OH)、-C(O)NH(CN)、-C(O)NHSO2RG3a、-SO2NHC(O)RG3a、-C(O)NHSO2NHRG3a、-C(O)NHSO2N
(RG3a)2、-SO2NH2、-SO2NHRG3a、-SO2N(RG3a)2、-C(O)NHS(O)(RG3a)=NC (O) RG3a、-C(O)NHS(O)
(RG3a)=NRG3bOrWherein
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl, C1-C6Halogenated alkyl or
GA；
RG3bIt is hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl or GA；
GAIt is independently naphthenic base, cycloalkenyl, aryl or heteroaryl at each occurrence, is not take each independently
Generation or by 1,2 or 3 R being selected independentlyuWhat group replaced；Wherein
RuIt is independently C at each occurrence1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halogen, C1-C6Halogenated alkyl ,-
CN, oxo ,-NO2、-ORj、-OC(O)Rk、-OC(O)N(Rj)2、-S(O)2Rj、-S(O)2N(Rj)2、-C(O)Rk、-C(O)ORj、-C
(O)N(Rj)2、-N(Rj)2、-N(Rj)C(O)Rk、-N(Rj)S(O)2Rk、-N(Rj)C(O)O(Rk) or-N (Rj)C(O)N(Rj)2；
RjAt each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl or C1-C6Alkyl halide
Base；And
RkAt each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl or C1-C6Halogenated alkyl.
In another embodiment of formula (I), R2It is C (O) OH.In another embodiment of formula (I), R2It is-C (O)
NHSO2RG3aOr-C (O) NHSO2N(RG3a)2；RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkane
Base or GA；Also, GAIndependently naphthenic base at each occurrence, the naphthenic base be independently unsubstituted or by 1,2 or
3 R being selected independentlyuWhat group replaced；Wherein RuIt is independently C at each occurrence1-C6Alkyl.In the another of formula (I)
In a embodiment, R2It is-C (O) NHSO2RG3a；RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6
Alkyl or GA；Also, GAIndependently naphthenic base at each occurrence, the naphthenic base be independently unsubstituted or by 1,2,
Or 3 R being selected independentlyuWhat group replaced；Wherein RuIt is independently C at each occurrence1-C6Alkyl.In the another of formula (I)
In one embodiment, R2It is-C (O) NHSO2N(RG3a)2；And RG3aIt is independently C at each occurrence1-C6Alkyl.
In one embodiment of formula (I), R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6It is halogenated
Alkyl and C3-C6Naphthenic base.In another embodiment of formula (I), R2AIt is hydrogen or C1-C6Alkyl.In another of formula (I)
In embodiment, R2AIt is hydrogen.In another embodiment of formula (I), R2AIt is C1-C6Alkyl.In another embodiment of formula (I)
In, R2AIt is CH3。
In one embodiment of formula (I), R2It is C (O) OH；And R2AIt is hydrogen.
In one embodiment of formula (I),
R2It is-P (O) (OH)2、-P(O)(OH)(H)、-B(OH)2、-SO3H、-CH(OH)CF3、-C(O)NH(OH)、-C(O)
NH(CN)、-C(O)NHSO2RG3a、-SO2NHC(O)RG3a、-C(O)NHSO2NHRG3a、-C(O)NHSO2N(RG3a)2、-SO2NH2、-
SO2NHRG3a、-SO2N(RG3a)2、-C(O)NHS(O)(RG3a)=NC (O) RG3a、-C(O)NHS(O)(RG3a)=NRG3bOr
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl, C1-C6Halogenated alkyl or
GA；
RG3bIt is hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl or GA；
GAIt is independently naphthenic base, cycloalkenyl, aryl or heteroaryl at each occurrence, is not take each independently
Generation or by 1,2 or 3 R being selected independentlyuWhat group replaced；Wherein
RuIt is independently C at each occurrence1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halogen, C1-C6Halogenated alkyl ,-
CN, oxo ,-NO2、-ORj、-OC(O)Rk、-OC(O)N(Rj)2、-S(O)2Rj、-S(O)2N(Rj)2、-C(O)Rk、-C(O)ORj、-C
(O)N(Rj)2、-N(Rj)2、-N(Rj)C(O)Rk、-N(Rj)S(O)2Rk、-N(Rj)C(O)O(Rk) or-N (Rj)C(O)N(Rj)2；
RjAt each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl or C1-C6Alkyl halide
Base；
RkAt each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl or C1-C6Halogenated alkyl；And
And
R2AIt is hydrogen.In one embodiment of formula (I), R2It is-C (O) NHSO2RG3aOr-C (O) NHSO2N(RG3a)2；
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl or GA；
GAIt is independently naphthenic base at each occurrence, the naphthenic base is independently unsubstituted or by 1,2 or 3
The R being selected independentlyuWhat group replaced；
RuIt is independently C at each occurrence1-C6Alkyl；And
R2AIt is hydrogen.
In one embodiment of formula (I), R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base,
Phenyl and 5-6 unit's heteroaryl；The wherein R3 C1-C6Alkyl is optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: C1-C6Alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3 C3-C6Cycloalkanes
Base, phenyl and 5-6 unit's heteroaryl be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R3AIt is independent
Ground is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl.In another embodiment of formula (I)
In, R3It is selected from the group, which is made up of: C1-C6Alkyl and C3-C6Naphthenic base；The wherein R3 C1-C6Alkyl is optionally by one
A or multiple C1-C6Alkoxy replaces；The wherein R3 C3-C6Naphthenic base is optionally by one or more C1-C6Alkyl replaces；And
And R3AIt is independently hydrogen.In another embodiment of formula (I), R3It is C1-C6Alkyl；The wherein R3 C1-C6Alkyl optionally by
One or more C1-C6Alkoxy replaces；And R3AIt is independently hydrogen.In another embodiment of formula (I), R3It is C3-C6Ring
Alkyl；The wherein R3 C3-C6Naphthenic base is optionally by one or more C1-C6Alkyl replaces；And R3AIt is hydrogen.In formula (I)
In one embodiment, R3It is CH3, and R3AIt is hydrogen.In one embodiment of formula (I), R3It is C (CH3)3, and R3AIt is hydrogen.
In one embodiment of formula (I), R3It is C (OCH3)(CH3)2, and R3AIt is hydrogen.In one embodiment of formula (I), R3It is
Cyclopropyl, the wherein R3Cyclopropyl is optionally by a CH3Replace；And R3AIt is hydrogen.In one embodiment of formula (I), R3It is
Two rings [1.1.1] pentyl, and R3AIt is hydrogen.
In one embodiment of formula (I), R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；Wherein by
R3And R3AAnd C that the carbon attached by them is formed3-C6Naphthenic base is optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2、F、
Cl, Br and I.In another embodiment of formula (I), R3And R3AUnsubstituted C is formed together with the carbon attached by them3-C6Ring
Alkyl.In another embodiment of formula (I), R3And R3ACyclopropyl is formed together with the carbon attached by them.
In one embodiment of formula (I), R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 member
Heteroaryl, L1- 4-12 circle heterocyclic ring base, L1-C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4 C6-C10Aryl, 5-
11 unit's heteroaryls, 4-12 circle heterocyclic ring base, C3-C11Naphthenic base and C4-C11Cycloalkenyl is optionally independently selected by one or more
Replace from the substituent group of the following group, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、
SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；Wherein L1It is not present, or is selected from the group, which is made up of: C1-
C6Alkylidene, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Sub- alkene
Base and C2-C6Alkynylene is optionally independently selected by one or more from the following group either individually or as a part of group
Substituent group replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And R4AIt is selected from the group, the group is by with the following group
At: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl.In another embodiment of formula (I), R4It is selected from the group, the group is by following
Composition: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring base and L1-C3-C11Naphthenic base；The wherein R4
C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base and C3-C11Naphthenic base is optionally independently selected by one or more
Replace from the substituent group of the following group, which is made up of: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9、
OH, CN, F, Cl and Br；Wherein L1It is not present or is selected from the group, which is made up of: C1-C6Alkylidene, C2-C6Alkenylene,
C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene and C2-C6Alkynylene, it is single
Solely or as group a part, be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkoxy, OH and oxo；And R4AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl.?
In another embodiment of formula (I), R4It is L1-C6-C10Aryl；The wherein R4 C6-C10Aryl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、
SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.In another embodiment of formula (I), R4
It is L1- 5-11 unit's heteroaryl；The wherein R45-11 unit's heteroaryl is optionally independently selected by one or more from the substituent group of the following group
Replace, which is made up of: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；
Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.In another embodiment of formula (I), R4It is L1- 4-12 circle heterocyclic ring base；Its
In the R4The substituent group that 4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylene
Base；And R4AIt is hydrogen.In another embodiment of formula (I), R4It is L1-C3-C11Naphthenic base；The wherein R4 L1-C3-C11Cycloalkanes
The substituent group that base is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、
SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.In formula
(I) in one embodiment, R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；The wherein 4-12 circle heterocyclic ring
The substituent group that base is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、C
(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I.In another of formula (I)
In embodiment, R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base is optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: OR9And Cl.
In one embodiment of formula (I), R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Virtue
Base, (C1-C6Alkylidene)x- 5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-C11
Naphthenic base and (C1-C6Alkylidene)x-C4-C11Cycloalkenyl；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-C10
First aryl, (C1-C6Alkylidene)xThe 5-11 unit's heteroaryl of -5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base
4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-C11The C of naphthenic base3-C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11Ring
The C of alkenyl4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, which is made up of:
R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；And x is 0 or 1.In formula (I)
In another embodiment, R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6Alkylene
Base)x- 5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base and (C1-C6Alkylidene)x-C3-C11Naphthenic base；Its
In the R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)xThe 5-11 of -5-11 unit's heteroaryl
Unit's heteroaryl, (C1-C6Alkylidene)xThe 4-12 circle heterocyclic ring base and (C of -4-12 circle heterocyclic ring base1-C6Alkylidene)x-C3-C11Cycloalkanes
The C of base3-C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of:
R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；AndxIt is 0 or 1.?
In another embodiment of formula (I), R4It is (C1-C6Alkylidene)x-C6-C10Aryl；The wherein R4(C1-C6Alkylidene)x-C6-C10
The substituent group that first aryl is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)
OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；AndxIt is 0 or 1.
In another embodiment of formula (I), R4It is (C1-C6Alkylidene)x- 5-11 unit's heteroaryl；The wherein R4(C1-C6
Alkylidene)xThe substituent group that -5-11 unit's heteroaryl is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；AndxIt is 0
Or 1.In another embodiment of formula (I), R4It is (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base；The wherein R4(C1-C6Alkylene
Base)xThe substituent group that -4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of:
R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0 or 1.?
In another embodiment of formula (I), R4It is (C1-C6Alkylidene)x-C3-C11Naphthenic base；The wherein R4(C1-C6Alkylidene)x-C3-
C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C
(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0 or 1.
In one embodiment of formula (I), R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 member are miscellaneous
Aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5 C6-C10
First aryl, 5-11 unit's heteroaryl, the 4-6 unit monocycle heterocycle condensed with phenyl group, C3-C11Naphthenic base and C4-C11Cycloalkenyl
The substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14、OH、
Oxo, CN, NO2, F, Cl, Br and I；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl,
C1-C6Halogenated alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
Base and 4-12 circle heterocyclic ring base；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R13And R14Every
Secondary is hydrogen or C each independently when occurring1-C6Alkyl.In another embodiment of formula (I), R5Be selected from the group, the group by with
Lower composition: C6-C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl；The wherein R5 C6-
C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl are optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12Occurring every time
When independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 member
Heterocycle；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In another embodiment of formula (I), R5
It is selected from the group, which is made up of: C6-C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 member
Heteroaryl；The wherein R5 C6-C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14、OH、F、
Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-
C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R12 C3-C11Naphthenic base and 4-12 circle heterocyclic ring base optionally by one or
Multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkyl halide
Base, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；And R13And R14Going out every time
It is now C each independently1-C6Alkyl.
In one embodiment of formula (I), R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 member are miscellaneous
Aryl, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5 C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base and C4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and I；R12At each occurrence independently selected from the following group, the group
It is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl,
C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl,
C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2、F、
Cl, Br and I；And R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl.In another implementation of formula (I)
In example, R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 unit's heteroaryl；The wherein R5 C6-C10First aryl
The substituent group for being optionally independently selected by one or more from the following group with 5-11 unit's heteroaryl replaces, which is made up of: R12、
OR12、NR13R14, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-
C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-
C6Alkyl.In another embodiment of formula (I), R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 member are miscellaneous
Aryl；The wherein R5 C6-C10First aryl and 5-11 unit's heteroaryl are optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: R12、OR12、NR13R14, F, Cl and Br；R12It, should at each occurrence independently selected from the following group
Group is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R12
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base be optionally independently selected by one or more from the following group substituent group replace, the group by
Consisting of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R13With
R14It is C each independently at each occurrence1-C6Alkyl.
In another embodiment of formula (I), R5It is C6-C10First aryl；The wherein R5 C6-C10First aryl is optionally by one
A or multiple substituent groups independently selected from the group below replace, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Cycloalkanes
Base and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In the another of formula (I)
In a embodiment, R5It is the 4-6 unit monocycle heterocycle condensed with phenyl group；The wherein R5, i.e., first with the condensed 4-6 of phenyl group
Monocyclic heterocycles, the substituent group for being optionally independently selected by one or more from the following group replace, which is made up of: R12、OR12、
NR13R14, OH, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6
Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-C6
Alkyl.In another embodiment of formula (I), R5It is 5-11 unit's heteroaryl；The wherein R55-11 unit's heteroaryl is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12
At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base,
And 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In another of formula (I)
In embodiment, R5It is 5-11 unit's heteroaryl；The wherein R55-11 unit's heteroaryl is optionally independently selected by one or more from the following group
Substituent group replace, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12It independently selects at each occurrence
From the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Its
In each R12 C3-C11The substituent group that naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group takes
Generation, the group are made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkane
Base)2, OH, oxo, CN, NO2, OH, F, Cl, Br and I；And R13And R14It is C each independently at each occurrence1-C6Alkyl.
In another embodiment of formula (I), R5It is unsubstituted phenyl.In another embodiment of formula (I), R5It is
Phenyl；The wherein R5The substituent group that phenyl is optionally independently selected by one or more from the following group replaces, which is made up of:
R12、OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkane
Base, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is respectively independent at each occurrence
Ground is C1-C6Alkyl.In another embodiment of formula (I), R5It is phenyl；The phenyl is by a R12Replace；And R12It is C1-
C6Alkyl.In another embodiment of formula (I), R5It is phenyl；The phenyl is by a R12Replace；And R12It is CH3Or CH
(CH3)2.In another embodiment of formula (I), R5It is pyridyl group；The pyridyl group is optionally independently selected by one or more from
The substituent group of the following group replaces, which is made up of: R12、OR12And NR13R14；R12It is independently C1-C6Alkyl；And R13
And R14It is C each independently at each occurrence1-C6Alkyl.In another embodiment of formula (I), R5It is pyridyl group；The pyrrole
The substituent group that piperidinyl is optionally independently selected by one or more from the following group replaces, which is made up of: R12、OR12And
NR13R14；R12It is independently CH3Or CH (CH3)2；And R13And R14It is CH each independently at each occurrence3.In formula (I)
In another embodiment, R5It is pyridyl group；The wherein R5Pyridyl group is optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence independently selected under
Group, the group are made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13
And R14It is C each independently at each occurrence1-C6Alkyl.
In one embodiment of formula (I), R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-
C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein
The R6 C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally independently selected by one or more from the substituent group of the following group
Replace, which is made up of: R15、OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、
SO2R18、NR19R20, OH, oxo, CN, NO2, F, Cl, Br and I；R15At each occurrence independently selected from the following group, the group by with
Lower composition: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11
Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R15 C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally by one
A or multiple substituent groups independently selected from the group below replace, which is made up of: OH, oxo, CN, NO2, F, Cl, Br and I；
Wherein each R156-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alcoxyl
Base, C1-C6Halogenated alkyl, oxo, OH, CN, NO2, F, Cl, Br and I；R16And R17Be each independently at each occurrence hydrogen or
C1-C6Alkyl；And R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl,
C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Its
In each R18 C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-
C11Cycloalkenyl and 4-12 circle heterocyclic ring base be optionally independently selected by one or more from the following group substituent group replace, the group by
Consisting of: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I.In formula (I)
In another embodiment, R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6 C1-C6Alkyl is appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: R15、OR15、SR15, OH and
F；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C(O)R18、C(O)
OR18、SO2R18, OH, oxo, CN, F and Cl；R15At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C2-C6Alkenyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
Ring group；Wherein each R156-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；
And R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18 C1-C6Alkyl and C6-C10First virtue
The substituent group that base is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6
Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl.
In one embodiment of formula (I), R6It is C1-C6Alkyl；The wherein R6 C1-C6Alkyl is optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R15、OR15、SR15, OH and F；And R15Each
Independently selected from the following group when appearance, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-
11 unit's heteroaryls, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member aryl, 5-
11 unit's heteroaryls, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more
Replace from the substituent group of the following group, which is made up of: C1-C6Alkyl, OH, CN, F and Cl.In another implementation of formula (I)
In example, R6It is C1-C6Alkyl；The wherein R6 C1-C6Alkyl is by a R15Replace；And R15It is independently 6- at each occurrence
10 yuan of aryl.In another embodiment of formula (I), R6It is C2Alkyl；The wherein R6 C2Alkyl is by a R15Replace；And R15
It is independently phenyl at each occurrence.In another embodiment of formula (I), R6It is C1-C6Alkyl；The wherein R6 C1-C6Alkane
Base is unsubstituted.In another embodiment of formula (I), R6It is-CH3.In another embodiment of formula (I), R6It is-CH
(CH3)2.In one embodiment of formula (I), R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring base is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: R18、OR18、C(O)R18、C(O)OR18、SO2R18、
OH, oxo, CN, F and Cl；And R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkane
Base, C2-C6Alkenyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl and C6-C10First aryl be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl.In another embodiment of formula (I), R6
It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring base is unsubstituted.In another embodiment of formula (I), R6It is tetrahydro
Furyl.In another embodiment of formula (I), R6It is THP trtrahydropyranyl.In one embodiment of formula (I), R6It is C3-C11
Naphthenic base；The wherein R6 C3-C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, the group
It is made up of: R18、OR18、C(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；And R18Occurring every time
When independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-11 unit's heteroaryl,
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10First aryl is optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl,
CN, F and Cl.In another embodiment of formula (I), R6It is C3-C11Naphthenic base；The wherein R6 C3-C11Naphthenic base is optionally
Replaced by one or more F.In another embodiment of formula (I), R6It is C3-C11Naphthenic base；The wherein C3-C11Naphthenic base is
It is unsubstituted.In another embodiment of formula (I), R6It is cyclohexyl；The wherein R6Cyclohexyl is replaced by two F.At formula (I)
Another embodiment in, R6It is cyclopenta.In another embodiment of formula (I), R6It is cyclohexyl.
In one embodiment of formula (I), R1It is C (O) OR6；R6It is C1-C6Alkyl；The wherein R6 C1-C6Alkyl is optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: R15、OR15、SR15, OH and F；And
And R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-
10 yuan of aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R15 6-
10 yuan of aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base optionally by one or
Multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl.
In one embodiment of formula (I), R1It is C (O) OR6；And R6It is C1-C6Alkyl；The wherein R6It is unsubstituted
C1-C6Alkyl.
In one embodiment of formula (I), R1It is C (O) R6；R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring base
The substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C(O)R18、C
(O)OR18、SO2R18, OH, oxo, CN, F and Cl；And R18At each occurrence independently selected from the following group, the group is by following
Composition: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring
Base；Wherein each R18C1-C6Alkyl and C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl.
In one embodiment of formula (I), R1It is C (O) R6；And R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 member is miscellaneous
Ring group is unsubstituted.
In one embodiment of formula (I), R9At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and
4-12 circle heterocyclic ring base；Wherein each R9 C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)
NR22R23、SO2R21、NR22R23, OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxygen
Generation, CN, NO2, F, Cl, Br and I；R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-
C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
Ring group；Wherein each R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces,
The group is made up of: OH, oxo, CN, NO2, F, Cl, Br and I；R22And R23Be each independently at each occurrence hydrogen or
C1-C6Alkyl；R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；And R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
In another embodiment of formula (I), R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl,
6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9 C1-C6Alkyl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R21、OR21、C(O)OR21、
NR22R23, OH, CN and F；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 member are miscellaneous
The substituent group that ring group is optionally independently selected by one or more from the following group replaces, which is made up of: R24、OR24、CN、F、
And Cl；R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21 C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally one or more
CN replaces；R22And R23It is C each independently at each occurrence1-C6Alkyl；And R24At each occurrence independently selected under
Group, the group are made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base.
In one embodiment of formula (I), R10And R11Be each independently selected from the following group at each occurrence, the group by with
Lower composition: hydrogen, C1-C6Alkyl, phenyl and 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy,
C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I.In another embodiment of formula (I), R10And R11Every
Secondary to be each independently selected from the following group when occurring, which is made up of: hydrogen and 5-6 unit's heteroaryl；Wherein each R10And R11 5-6
Unit's heteroaryl is optionally by one or more C1-C6Alkoxy replaces.
In one embodiment of formula (I), R4It is (C1-C6Alkylidene)x-C6-C10Aryl；The wherein R4(C1-C6Alkylene
Base)x-C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group replaces, which is made up of: R9
And OR9；R4AIt is hydrogen；X is 0 or 1；And R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl
And C3-C11Naphthenic base；Wherein each R9 C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Naphthenic base is optional
Ground is by one or more R24Replace；And R24It is independently C at each occurrence1-C6Alkyl.In one embodiment of formula (I)
In, R4It is L1-C6-C10Aryl；The wherein R4 C6-C10First aryl is optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: R9And OR9；Wherein L1It is not present or C1-C6Alkylidene；R4AIt is hydrogen；And R9Each
Independently selected from the following group when appearance, which is made up of: C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9 C1-C6Alkyl
Optionally replaced by one or more F；Wherein each R9Naphthenic base is optionally by one or more R24Replace；And R24Each
It is independently C when appearance1-C6Alkyl.
In another embodiment of formula (I), R4It is CH2Phenyl；The wherein R4 CH2Phenyl is optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence
Independently selected from the following group, which is made up of: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；It is wherein every
A R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optionally by one or more CH3Replace.In another of formula (I)
In embodiment, R4It is phenyl；The wherein R4The substituent group that phenyl is optionally independently selected by one or more from the following group replaces, should
Group is made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, which is made up of:
CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and two rings
[1.1.1] amyl is optionally by one or more CH3Replace.
In another embodiment of formula (I), R4It is (C1-C6Alkylidene)x- 5-11 unit's heteroaryl；The wherein R4(C1-C6
Alkylidene)xThe substituent group that -5-11 unit's heteroaryl is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9And OR9；R4AIt is hydrogen；X is 0 or 1；And R9At each occurrence independently selected from the following group, which is made up of:
C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9 C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Ring
Alkyl is optionally by one or more R24Replace；And R24It is independently C at each occurrence1-C6Alkyl.In the another of formula (I)
In one embodiment, R4It is L1- 5-11 unit's heteroaryl；The wherein R45-11 unit's heteroaryl optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R9And OR9；L1It is not present or C1-C6Alkylidene；R4AIt is hydrogen；R9
At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9
C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Naphthenic base is optionally by one or more R24Replace；And
R24It is independently C at each occurrence1-C6Alkyl.
In another embodiment of formula (I), R4It is CH2Pyridyl group；The wherein R4 CH2Pyridyl group is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: R9And OR9；R4AIt is hydrogen；And R9Going out every time
Now independently selected from the following group, which is made up of: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Its
In each R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optionally by one or more CH3Replace.In the another of formula (I)
In one embodiment, R4It is pyridyl group；The wherein R4Pyridyl group is optionally independently selected by one or more from the substituent group of the following group
Replace, which is made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, the group is by following
Composition: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and two
Ring [1.1.1] amyl is optionally by one or more CH3Replace.In another embodiment of formula (I), R4It is CH2Quinolyl；
The wherein R4 CH2The substituent group that quinolyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, which is made up of: CH3、CF3, cyclopropyl
Base, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optional
Ground is by one or more CH3Replace.
In one embodiment of formula (I), R4It is selected from the group, which is made up of:
Wherein RxIt is selected from the group, which is made up of: CH3And OCH3, and RyIt is selected from the group, it should
Group is made up of: CF3、CH3、C(CH3)3, cyclopropyl, by CH3Substituted cyclobutyl and two rings [1.1.1] amyl；And n
It is 0 or 1.
One embodiment is related to the compound with (I),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl；
R3It is selected from the group, which is made up of: C1-C6Alkyl and C3-C6Naphthenic base；The wherein R3 C1-C6Alkyl is optional
Ground is by one or more C1-C6Alkoxy replaces；The wherein R3 C3-C6Naphthenic base is optionally by C1-C6Alkyl replaces；And
R3AIt is hydrogen；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；
R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6Alkylidene)x-5-11
Unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base and (C1-C6Alkylidene)x-C3-C11Naphthenic base；The wherein R4(C1-
C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)xThe 5-11 unit's heteroaryl of -5-11 unit's heteroaryl,
(C1-C6Alkylidene)xThe 4-12 circle heterocyclic ring base and (C of -4-12 circle heterocyclic ring base1-C6Alkylidene)x-C3-C11The C of naphthenic base3-C11
The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)
OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；
R4AIt is hydrogen；
R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 unit's heteroaryl；The wherein R5 C6-C10First virtue
The substituent group that base and 5-11 unit's heteroaryl are optionally independently selected by one or more from the following group replaces, which is made up of:
R12、OR12、NR13R14, F, Cl and Br:
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6 C1-C6Alkyl, C2-C6Alkenyl,
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15, OH and F；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-
The substituent group that 12 circle heterocyclic ring bases are optionally independently selected by one or more from the following group replaces, which is made up of: R18、
OR18、C(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9 C1-C6Alkyl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)OR21、NR22R23, OH, CN and F；Its
In each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R24、OR24, CN, F and Cl；
R10And R11It is each independently selected from the following group at each occurrence, which is made up of: hydrogen and 5-6 unit's heteroaryl；
Wherein each R10And R115-6 unit's heteroaryl is optionally by one or more C1-C6Alkoxy replaces；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；
R13And R14It is C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, 6-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10
First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10Member
The substituent group that aryl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21 C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally replaced by CN；
R22And R23It is C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base；And
X is 0 or 1.
One embodiment is related to the compound with (I),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl；
R3It is selected from the group, which is made up of: C1-C6Alkyl and C3-C6Naphthenic base；The wherein R3 C1-C6Alkyl is optional
Ground is by one or more C1-C6Alkoxy replaces；The wherein R3 C3-C6Naphthenic base is optionally by C1-C6Alkyl replaces；And
R3AIt is hydrogen；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring
Base and L1-C3-C11Naphthenic base；The wherein R4 C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base and C3-C11Ring
The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)
OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1Be not present, or be selected from the group, the group by with
Lower composition: C1-C6Alkylidene, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylene
Base, C2-C6Alkenylene and C2-C6Alkynylene, either individually or as a part of group, optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: OR9And Cl；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl and condensed with phenyl group
4-6 unit monocycle heterocycle；The wherein R5 C6-C10First aryl, 5-11 unit's heteroaryl and the 4-6 member list condensed with phenyl group
The substituent group that ring heterocycle is optionally independently selected by one or more from the following group replaces, which is made up of: R12、OR12、
NR13R14, OH, F, Cl and Br；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6 C1-C6Alkyl, C2-C6Alkenyl,
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15, OH and F；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-
The substituent group that 12 circle heterocyclic ring bases are optionally independently selected by one or more from the following group replaces, which is made up of: R18、
OR18、C(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9 C1-C6Alkyl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)OR21、NR22R23, OH, CN and F；Its
In each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R24、OR24, CN, F and Cl；
R10And R11It is each independently selected from the following group at each occurrence, which is made up of: hydrogen and 5-6 unit's heteroaryl；
Wherein each R10And R115-6 unit's heteroaryl is optionally by one or more C1-C6Alkoxy replaces；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R12 C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6It is halogenated
Alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, 6-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10
First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10Member
The substituent group that aryl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally replaced by CN；
R22And R23It is C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
Exemplary compounds with formula (I) include but is not limited to:
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl)
Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methoxyl group -4- (fluoroform
Base) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -2-
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -2-
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- { [6- methyl -
4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2R*) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (difluoro-methoxy) phenyl] -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (benzenesulfonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl 1-1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(is disliked
Alkane -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2S*, 3S*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyl group -5- phenylpyridine -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S) -
3,3- difluorocyclohex alkane -1- carbonyls] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -
3,3- difluorocyclohex alkane -1- carbonyls] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2- methoxyl group -3- phenylpropionyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) ring
Propyl] phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cis- -
4- hydroxyl -4- propyl cyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (two
Methylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] pyrroles
Alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -5-
[2- (dimethylamino) pyridin-3-yl] -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -3,4- dihydro -2H-1- chromene -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(1S*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- first
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trimethyl silyl
Base) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -5- methoxypyridine -4- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorine
Phenyl) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (2,2,6,6- tetramethyl oxane -4- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(5- tert-butyl -2- methoxypyridine -3- base) amino] -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- hydroxyl -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -
5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl)-N- (mesyl) -5- Phenylpyrrolidine -2- formamide；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [4- (3- chlorphenyl) oxane -4- base] methyl } amino) -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(6- tert-butyl -2- methoxypyridine -3-
Base) methyl] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S*,
2R*, 4R*) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- (2- methoxypyridine -3- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- { [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- { [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (3- chlorine
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl]
Methyl } amino) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -
5- (2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- ring
PropyIpyridine -3- base) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (ethoxy carbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (Cyclopentanecarbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- [(2S)-oxygen penta
Ring -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -1- (cyclobutanecarbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- chlorphenyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxypyridine -3-
Base) methyl] amino } -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- ring
Propyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
5- (2- aminomethyl phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Base phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- ethylphenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (1- methyl ring fourth
Base) phenyl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl]
Amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2,2- dimethyl -2,3- dihydro -1- benzo furans
Mutter -7- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] (methyl) ammonia
Base } -1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [(4,6- dimethoxypyridin -2-
Base) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(4- chloro-6-methoxylpyrimidin -2- base) amino] -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [1- (2,2- bis- fluoro- 2H-1,3-
Benzodioxole -5- base) ethyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- methoxyl group -1,3- diformazan
Base -1H- pyrazoles -4- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [4- (trifluoromethyl)
Pyrimidine -2-base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- cyclopropyl -4- { [6- methyl -4- (trifluoromethyl)
Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ 1- [2- methoxyl group -5- (trifluoro
Methyl) phenyl] ethyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(2,6- dimethoxypyridin -4-
Base) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methoxyl group -4- (trifluoromethyl) pyridine -2- base] ammonia
Base } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) phenyl]
Methyl } amino) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [4- methyl -6- (trifluoromethyl) pyrimidine -2-base] amino } -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) -5- first
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) phenyl]
Methyl } amino) -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(4R, 6R, 7R) -5- (cyclohexane carbo) -7- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] ammonia
Base } -6- phenyl -5- azaspiro [2.4] heptane -4- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -5-
(6- methoxypyridine -2- base) -1- (oxane -2- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (6- methoxypyridine -2- base) -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- (difluoro-methoxy) pyridine -
2- yl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) phenyl] -
4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- [oxane -2- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- (3- oxabicyclo [3.1.0] hexane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- [oxane -2- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [(dislike by 2,2- dimethyl
Alkane -4- carbonyl] -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(3R) -1- (methoxycarbonyl) piperidines -3- carbonyl] -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (mesyl) -2- methoxy
Base phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- [(2S*) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
(2R*, 3R*, 4R*, 5R*) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -
4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (propane -2-
Base) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxypyridine -3- base of 5-) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -
5- phenyl -1- (spiral shell [2.5] octane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- { [6- methoxy
Base -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- first
Oxygroup -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (3-Methoxy Pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (2- methoxyl group -2- methylpropionyl) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3- methoxynaphthalene -2- base) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (difluoro-methoxy) phenyl] -4- ({ [2-
Methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(1- benzofuran -2- base) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,3- dihydros-Isosorbide-5-Nitrae-benzo dioxin -6-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (cyclo propyl methoxy) -4- fluorophenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- chlorine-2-hydroxyl phenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [6- (propane -2- base) -4- (three
Methyl fluoride) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(3- cyano -4- methoxy quinoline -2- base) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- [3- (trifluoromethyl) anilino-] pyrrole
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S,
3S) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S, 3S) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- benzoyl -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,1-
- 1 λ of dioxo6Vulcanize pentamethylene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [6- cyclobutyl -4- (trifluoromethyl) pyridine -2- base] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- benzyl -2- methoxypyridine -3- base) methyl] amino } -3- tert-butyl -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (butane -2- base) -2- methoxypyridine -3- base] methyl } amino) tertiary fourth of -3-
Base -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxyl group pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxypyridine -3-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxypyridine -3-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2- ethyl-butyl) -2- methoxyl group pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- phenylethyl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methyl-propyl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 5- [(3- cyano-phenyl) methyl] -2- methoxypyridine -3- base } first
Base) amino] -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base) methyl] amino } -1-
[(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- hydroxy phenyl) methyl] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- methoxybenzene amido) -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -3,4- dihydro -2H-1- chromene -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
[(oxane -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 5- [(dimethylamino) methyl] -2- first
Phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (five fluoro- λ6Sulfane
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base) methyl] ammonia
Base } -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (2- dicyanopropane -2- base) -2- methoxyphenyl] methyl } ammonia
Base) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- (2- hydroxy propane -2- base) -2- methoxy
Base phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (5- cyanogen
Base -2- methoxybenzoyl base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1,3-
Dihydro -2H- iso-indoles -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(sulphur benzene -3- base) acetyl group] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- fluorine
Quinoline -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methyl-propyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2- cyclopropyl -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2- cyclopropyl -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [(1S, 3s)-tricyclic
[3.3.1.1S,7] decane -1- base] phenyl methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1H-
Imidazol-4 yl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- hydroxyl
Cyclopentyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- [(azepan -1- base) acetyl group] -3- tert-butyl -4- { [(5- tert-butyl -2- first
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- second
Base -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- first
Base -4H- furans simultaneously [3,2-b] pyrroles -5- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (4-
Chloro- 1H- pyrazol-1-yl) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2R*, 3R*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2R*, 3R*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2S*, 3S*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(3aR*, 6aS*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(3aR*, 6aS*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- ({ [2- methoxyl group -5-
(propane -2- base) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5-
(propane -2- base) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (4- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methoxy propane -
2- yl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyrimidine -5- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene carbonyl
Base) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxypyridine -3- base) methyl] ammonia
Base } -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxyphenyl] methyl } amino) -
1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxyphenyl] methyl } ammonia
Base) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(ring penta
Base oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyrrolidin-1-yl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (piperidin-1-yl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyridazine -4- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 '-fluoro- 4- methoxyl groups [1,1 '-biphenyl] -
3- yl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,4- dimethyl -1,3-thiazoles -5-
Base) -2- methoxyphenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 '-cyano -4- methoxyl groups [1,1 '-biphenyl] -3- base) methyl] ammonia
Base } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (3,6- dihydro -2H- pyrans -4- base) -
2- methoxyphenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (4- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxypyridine -3-
Base) methyl] amino } -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxypyridine -3- base] methyl } ammonia
Base) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 3-Methoxy Pyridine -2- base of 6-) methyl] amino } -3- tert-butyl -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -3- (1- methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (first
Sulfonyl) piperidines -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(trans-) -2- (pyridin-3-yl) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2- fluorophenyl) -2- methoxypyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl } methyl)
Amino] -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (pyrazolo [1,5-a] pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [5- second
Base -1- (6- methoxyl group pyridazine -3- base) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [uncle 1-
Butyl -5- (propane -2- base) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (2-
Fluorophenyl) -3,5- dimethyl -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,5-
Dimethyl -2,3- dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- hydroxyl
Tetramethylcyclobutyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- [2- (azetidine -1- carbonyl) hexamethylene -1- carbonyl] -3- tert-butyl -4- { [(5-
Tert-butyl -2- methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [cis- -
4- hydroxyl -4- (propyl- 2- alkene -1- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cis- -
4- ethyl -4- hydroxycyclohexan -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [cis- -
4- hydroxyl -4- (propane -2- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (benzene oxygen
Base carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(2-
Chlorphenyl) methoxyl group] carbonyl } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (1- cyano cyclobutyl) -2- methoxyphenyl] methyl } amino) -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 2, the 3- dihydro -1H- indenes -2- base of 4-) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 2, the 3- dihydro -1H- indenes -2- base of 5-) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 2, the 3- dihydro -1H- indenes -1- base of 5-) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2- (3,4- difluorophenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [hexamethylene
Base (methoxyl group) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -3- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [3- (trifluoromethyl) pentamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (5,5- dimethyl butyl oxide link -2- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2,3- dihydros-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- cyclobutyl -5- methoxypyridine -4- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- cyclopenta -5- methoxypyridine -4-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 3- methoxyl group -6- [1- (trifluoromethyl) ring
Propyl] pyridine -2- base } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trimethyl silyl
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- oxygen
Miscellaneous two ring [3.2.1] octane -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (two
Methylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] pyrroles
Alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5-
[1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(oxane -2- carbonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2R*, 3R*) -3- phenyl butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2S*, 3S*) -3- phenyl butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(3,3- difluorocyclohex alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
Phenyl -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [(trifluoromethyl) sulfane
Base] phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -3- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- first
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxynaphthalene -1- base) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
5- (trimethyl silyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- { [(6- methoxyl group -
2,3- dihydro -1H- indenes -5- bases) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(3S*) -1- methyl -2- oxo-piperidine -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,1-
- 1 λ of dioxo6Thiophane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
{ (2S*) -2- [(2S*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
{ (2R*) -2- [(2R*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(3- methoxycyclohexyl alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*, 3S*) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3-
Dihydro-Isosorbide-5-Nitrae-benzo dioxin -6- carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [4- (ring
Hexyl oxygroup) benzoyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- first
Phenyl) methyl] amino } -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl)-N- (mesyl) -5- Phenylpyrrolidine -2- formamide；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(1R*, 2R*, 3R*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -
2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S*) -2,3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(3,4- dihydro -1H-2- chromene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -4- methoxy pyrimidine -5- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
1- (cyclohexane carbo) -2- methyl -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- methoxyl group -2- (pyrrolidin-1-yl) pyrrole
Pyridine -4- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1,1,1- tri- fluoro- 2-
Methylpropane -2- base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [2- (propane -2- base) butyl oxide link -3- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [4- (2- chlorphenyl) oxane -4- base] methyl } amino) -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethylamino)
Pyridin-3-yl] -3- (2- methoxy propane -2- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorine
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -5- [2- (dimethylamino) pyrrole
Pyridine -3- base] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(1S*, 2S*, 3S*, 4R*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl
Base] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- (2- methoxypyridine -3- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (difluoro-methoxy) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- [2- (difluoro-methoxy) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (difluoro-methoxy) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- fluorophenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (tert-butoxycarbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- methoxypyridine -3- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- cyclobutyl -2- methoxypyridine -3-
Base) methyl] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl)
Phenyl] methyl } amino) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] methyl } amino) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S*,
2R*, 4R*) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- first
Oxygroup pyridin-3-yl) methyl] amino } -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(oxygen
Azetidine -3- base) oxygroup] carbonyl } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(five fluoro- λ6Sulfanyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(3R) -1- { [(propane -2- base) oxygroup] carbonyl } piperidines -3- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- chloropyridine -3- base) methyl] amino } -1-
[(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- (1- cyclo-propane -1- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -
1- { [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- { [(propane -2-
Base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(3- methoxyl group -5,5,
8,8- tetramethyls -5,6,7,8- naphthane -2- bases) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2-
Formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (3- chlorphenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- [(2S) -2- Phenylbutanoyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(7R) -
2,2- bis- fluoro- 7- methyl -6,7- dihydro -2H- furans simultaneously [2,3-f] [1,3] benzodioxole -7- carbonyl] -5-
(2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- (2- methoxyl group pyrrole
Pyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- (2- methoxyl group pyrrole
Pyridine -3- base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
Phenyl -1- [(1R*, 3S*) -3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
Phenyl -1- [(1S*, 3R*) -3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Base phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -5- (2- aminomethyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -4- [(2- phenylethyl) amino] -1- { [(propane -2- base) oxygen
Base] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(2- methyl -2- phenyl propyl) amino] -5- phenyl -1- { [(propane -
2- yl) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- aminomethyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- aminomethyl phenyl) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [4- (2- methoxyphenyl) oxane -4- base] methyl } amino) -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- [({ 1- [4- (three
Methyl fluoride) phenyl] piperidines -3- base } methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl pyridine -3- base) -4- ({ [2- methoxyl group -5- (fluoroform
Base) phenyl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [relative configuration-(1R, 2S, 4S) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- [2- (propane -2- base) benzene
Base] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclopropane carbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [1.1.1] pentane -1- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -4- { [(bromo- 2- ethoxybenzene of 5-
Base) methyl] amino } -3- tert-butyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ 3- [(2- methoxypyridine -3- base) ammonia
Base] cyclobutyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (ring fourth
Alkyl carbonyl) -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3-
Base) methyl] amino } -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl)
Phenyl] methyl } amino) -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- chlorphenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- hydroxy phenyl) methyl] amino } -1- [(2S)-oxygen
Penta ring -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -5- (2- first
Base phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] first
Base } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl]
Amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) benzene
Base] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- ethylphenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2,3- dihydro -1- benzofuran -7- base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- [(methoxyl group -5 3-,
6,7,8- naphthane -2- bases) methyl] amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(6- methoxypyridine -2- sulfonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2,2- dimethyl -2,3- dihydro -1- benzofuran -7- base) methyl]
Amino } -1- [(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2,2- dimethyl -2,3- dihydro -1- benzofuran -7- base) methyl]
Amino } -1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2,2- dimethyl -2,3- dihydro -1- benzofuran -7- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (chloro- 7- methoxyl group -1, the 3- dihydro -2H- iso-indoles -2- base of 4-) -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ 2- [2- methoxyl group -5- (trifluoromethyl) phenoxy group] ethyl } amino) -
1- { [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- hydroxy phenyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(5- chloropyridine -2- base) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- chloro- 4- (trifluoromethyl) pyridine -2- base] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 4- Dimethoxyphenyl of 3-) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- [({ 2- [(propane -2-
Base) oxygroup] phenyl } methyl) amino] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- methyl propoxyl group) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxypyridine -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 3-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [5- chloro- 2- (difluoro-methoxy) phenyl] methyl } ammonia
Base) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- chloro-2-ethoxy phenyl) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 6- methoxyphenyl of 2-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -1- [two (propane -2- base) carbamoyls] -3- methyl -4- { [6- methyl -4- (fluoroform
Base) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene carbonyl
Base) -3- cyclopropyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- chloro- 5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- chloro- 5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- (cyclohexane carbo) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) -4- first
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- [oxane -2- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- [oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- [oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2-
(dimethylamino) phenyl] -1- [oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [dislike by 2,2- dimethyl
Alkane -4- carbonyl] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2-
(dimethylamino) phenyl] -1- [2,2- dimethyl oxane -4- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2-
(dimethylamino) phenyl] -1- [2,2- dimethyl oxane -4- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(3S) -1- (methoxycarbonyl) piperidines -3- carbonyl] -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(fluoro- 2- methoxypyridine-of 5-
3- yl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (trifluoromethyl)
Phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- phenyl -1- (phenyl acetyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2-
Methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- [(2R, 3R) -2- methyl oxane -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- [(2S, 3S) -2- methyl oxane -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- ((2- methoxyl group -5- (trifluoromethyl) benzyl) amino) -
1- ((1R, 3R) -3- methoxycyclohexyl alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -
1- ((1R, 3R) -3- methoxycyclohexyl alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- ((the chloro- 2- methoxy-benzyl of 4-) amino) -1- ((1R,
3R) -3- methoxycyclohexyl alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the fluoro- 2- methoxyphenyl of 4-) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- methoxyl group -5- aminomethyl phenyl) methyl] amino } -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethoxy) phenyl] methyl }
Amino) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the fluoro- 2- methoxyphenyl of 5-) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (propane -2- base) phenyl] methyl } ammonia
Base) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- methoxyphenyl) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- [(2R) -2- methoxyl group -2- phenyl acetyl] pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2-
Methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- ((2S)-oxane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2-
Methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridine -3-
Base] -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridine -3-
Base] -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl)
Pyridine -2- base] amino } -5- (pyridine -2- base) pyrrolidines -2- formic acid；
(2S*, 3S*, 4S*, 5S*) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- [(2R) -
2- methoxyl group -2- phenyl acetyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -
5- phenyl -1- (phenyl acetyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- [(2S*) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- (butyl oxide link -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- (butyl oxide link -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (oxygen
Penta ring -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [(2R) -2- methoxyl group -2- phenyl
Acetyl group] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (dimethyl
Amino) phenyl] -1- [(2R) -2- methoxyl group -2- phenyl acetyl] pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- [(2R) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -1- [(2R*) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (4,4- difluorocyclohex alkane -1- carbonyl) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (4,4- difluorocyclohex alkane -1- carbonyl) -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- phenyl -1- (spiral shell [2.5] octane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- cyano -2- methoxyphenyl) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methyl -5- (trifluoromethyl)
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (propane -2-
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(4- cyano -2- methoxyphenyl) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [5- chloro- 2- (trifluoromethoxy) phenyl] methyl } ammonia
Base) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (trifluoro methoxy
Base) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -6- (fluoroform
Base) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene carbonyl
Base) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- phenyl -1- [(2S*) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2R)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -5- (2- methoxyl group pyrrole
Pyridine -3- base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Isosorbide-5-Nitrae-dioxanes -2- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (1,
4- dioxanes -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2- methoxyl group -
2- phenyl acetyl] -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- { [2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
1- [(cyclobutyl oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -4- (fluoroform
Base) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl]
Methyl } amino) -5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl]
Methyl } amino) -5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -4- (fluoroform
Base) phenyl] methyl } amino) -1- [(2R*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(1- benzofuran -3- base) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- Chloro-2-fluoro-5-methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,5- dichlorophenyl) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 5- methoxyphenyl of 2-) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- chloro- 2- (difluoro-methoxy) phenyl] methyl } amino) -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [3,5- bis- (trifluoromethyl) phenyl] methyl } amino) -3- tert-butyl -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- methoxyl group -2- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 5- methoxyphenyl of 2-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- dichlorophenyl) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 3- methoxyphenyl of 4-) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,4- dichlorophenyl) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the fluoro- 5- methoxyphenyl of the bromo- 4- of 2-) methyl] amino } -3- tert-butyl -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- difluorophenyl) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(dioxy between 6- methoxyl group -2H-1,3- benzo
Heterocyclic pentene -5- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,5- 3,5-dimethylphenyl) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 2- methoxyphenyl of 4-) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- ethyoxyl -2- aminomethyl phenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxy-propio] -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- tert-butyl-phenyl) methyl] amino } -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [3- (trifluoromethyl) phenyl] first
Base } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- methoxyl group -4- aminomethyl phenyl) methyl] amino } -5- (2- methoxy
Yl pyridines -3- base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (difluoro-methoxy) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3- methoxyl group -5,6,7,8- naphthane -2-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- ethoxyl phenenyl of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- methoxyl group -3- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4,5- difluoro-2-methoxy base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- ethyoxyl -2,3- dihydro -1H- indenes -5-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 3- Phenoxyphenyl of 4-) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,4- 3,5-dimethylphenyl) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- 3,5-dimethylphenyl) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- di-t-butyl phenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxyphenyl) -4- ({ [2- methoxyl group -4- (trifluoromethyl) benzene
Base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxyphenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) benzene
Base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- (2- methoxyl group
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyl group -4- aminomethyl phenyl) methyl]
Amino } -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- chloro- 2- (cyclo propyl methoxy) phenyl] methyl } amino) -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the fluoro- 4- methylquinoline -3- base of the chloro- 6- of 2-) amino] -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 5- cyanopyridine -3- base of 2-) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(3- cyano -6- picoline -2- base) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [3- cyano -4- (methoxy) -6- picoline -2- base] ammonia
Base } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- [3,5- bis- (trifluoromethyl) anilino-s] -3- tert-butyl -1- (cyclohexane carbo) -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R,
3R) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- benzoyl -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,1-
- 1 λ of dioxo6Vulcanize pentamethylene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- first
Base -1H- pyrazoles -3- sulfonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (benzenesulfonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (2,3- dihydros-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (propane -2- base) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [(2R) -3- methoxyl group -
2- methyl -3- oxopropyl] pyridin-3-yl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2- methyl propoxyl group) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(is disliked
Alkane -4- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,4- dihydro -2H-1- chromene -2- carbonyl) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -3,4- dihydro -2H-1- chromene -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4-
Dihydro -1H-2- chromene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (propane -2- base) phenyl]
Methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 3, the 4- dihydro -2H-1- chromene -4- base of 6-) amino] -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (propane -2- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (propane -2- base) phenyl] methyl } amino) -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -3- tert-butyl -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- second
Base -2- Methyl-1H-indole -3- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S,
2R, 4R) -4- (2- cyano ethyl) -2- methyl cyclopentane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- first
Base oxane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- cyanogen
Butylcyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(6,6-
Dimethyl oxane -3- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- [(two rings [1.1.1] pentane -1- base) acetyl group] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
{ [(1R) -3,4- dihydro -1H-2- chromene -1- base] acetyl group } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(is disliked
Alkane -3- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (phenyl acetyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- fluorine
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(sulphur benzene -2- base) acetyl group] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- chlorine
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(pyridin-3-yl) acetyl group] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (1- benzofuran -3- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxybenzene
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(pyrrolidin-1-yl) acetyl group] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4,4-
Difiuorocyclohexyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [1- (pyridine -2- base) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethoxy) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- benzyl -2- methoxyphenyl) methyl] amino } -3- tert-butyl -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxyphenyl) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxyphenyl) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- hydroxyl
Base phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- hydroxyl
Base phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,6-
Lutidines -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- first
Yl pyridines -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- fluorine
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,5-
Difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,6-
Difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,5-
Difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- first
Base phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- first
Base phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- first
Base phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- fluorine
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- first
Oxy-1-methyl-1 H- pyrazoles-5- carbonyl)-5- Phenylpyrrolidine-2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,5-
Dimethyl disulfide benzene -3- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(
Quinoline -4- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- hydroxyl
Butylcyclohexyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [2.2.1] hept- 5- alkene -2- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2-
Methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(ring
Hex- 2- alkene -1- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,4-
Dihydro -2H-1- chromene -4- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- first
Oxygroup hexamethylene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (2- phenylpropionyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [2- (propane -2- base) -1,3- dioxanes -5- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- oxygen
Generation -2,3- dihydro -1H- indenes -1- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,3-
Difluorocyclopentyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,2-
Difluorocyclopentyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,3-
Two fluoro- 1- methylcyclopentyls) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- first
Base -4- oxo -3,4- dihydro phthalazines -1- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3-
Dihydro -1- benzofuran -7- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
[5- is chloro- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
6- oxo -1- (propane -2- base) -1,6- dihydropyridine -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- { 4- [(pyridine -2- base) oxygroup] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- { 3- [(1H-1,2,4- triazol-1-yls) methyl] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- first
Base -3- phenyl -1H- pyrazoles -5- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- first
Base -5- phenyl -1H- pyrazoles -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [5- first
Base -1- (2- aminomethyl phenyl) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,5-
Dimethyl -1- phenyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4-
Dihydro -2H-1,5- benzodioxepins -7- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (2,1- benzoxazoles -3- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyl group
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4-
Dihydro -2H-1- chromene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,3-
Difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(ring
Amyl- 1- alkene -1- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(oxygen penta
Ring -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(5-
Chloro-3-fluoropyridine -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(R*) -
2- (the chloro- 3- methyl-1 H- pyrazol-1-yl of 4-) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [5- oxygen
Generation -1- (propane -2- base) pyrrolidines -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- ring
Propyl -5- oxo-pyrrolidine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- cyanogen
Base phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(3aR, 6aS)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -4-
({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (methoxy) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- [({ 2- methoxyl group -5-
[(1S, 3s)-tricyclic [3.3.1.13,7] decane -1- base] phenyl methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 methoxy quinoline -3- base) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- [(4- methoxyl group [1,
1 '-biphenyl] -3- base) methyl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyrrolidin-1-yl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -1- (cyclohexane carbo) -
3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -1- (cyclohexane carbo) -3- (2-
Methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxyl group -4 '-methyl [1,1 '-connection
Benzene] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methoxypyridine -
3- yl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxypyridine -3- base] methyl } ammonia
Base) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxypyridine -3- base) methyl] ammonia
Base } -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxypyridine -3- base] first
Base } amino) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5-
(propane -2- base) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- cyclobutyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxyphenyl) methyl] amino } -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxyphenyl) methyl] amino } -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5-
(propane -2- base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxypyridine -3-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene
Alkyl carbonyl) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- first
Base propoxyl group) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -4- ({ [2- first
Oxygroup -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -4- ({ [2- first
Oxygroup -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- first
Oxygroup -3- methylbutyryl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*,
3S*) -3- methyl butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*,
3R*) -3- methyl butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2- (3- chlorphenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2- (3- chlorphenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (2- methoxyl group -3- methylbutyryl) -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2R*, 3S*) -3- methyl butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (sulphur benzene -2- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (furans -3- base) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3 ', 4- dimethoxy [1,1 '-biphenyl] -
3- yl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (6- picoline -3-
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxyl group -2 '-methyl [1,1 '-connection
Benzene] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (4- picoline -3-
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3 '-cyano -4- methoxyl groups [1,1 '-biphenyl] -3- base) methyl] ammonia
Base } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(4 '-fluoro- -2 '-methyl of 4- methoxyl group [1,
1 '-biphenyl] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 ', 4 '-two fluoro- 4- methoxyl groups [1,1 ' -
Biphenyl] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyridin-3-yl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (3,5- dimethyl -1,2-oxazole -4-
Base) -2- methoxyphenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 ', 3 '-two fluoro- 4- methoxyl groups [1,1 ' -
Biphenyl] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (5- fluorine pyridin-3-yl) -2- methoxyl group
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- picoline -3-
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4 '-cyano -4- methoxyl groups [1,1 '-biphenyl] -3- base) methyl] ammonia
Base } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (1- cyclobutyl -1H- pyrazoles -4- base) -2- methoxyphenyl] first
Base } amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (furans -2- base) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (difluoro-methoxy) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,5-dihydrofuran -3- base) -2- first
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -5-
(2- methoxyphenyl) -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -3- (2- methoxy propane -2- base) -
4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3- methoxyl group -6- phenylpyridine -2- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2- methoxyl group -3,3- dimethylbutanoyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2- methoxyl group -3,3- dimethylbutanoyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,4- dihydro -1H-2- chromene -3- carbonyl) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4-
Dihydro -1H-2- chromene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2,6- difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3-
(1- methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -3- (1- methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (4,4,4- tri- fluoro- 2- methylbutyryl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (3-
Fluorophenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- first
Basic ring butane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (4-
Fluorophenyl) cyclopropane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
2- methoxy-propio] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,2-
Dimethylcyclopropane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (4-
Fluorophenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2- methoxy-propio] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (2-
Chlorophenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (ring fourth
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3-
Dihydro -1- benzothiophene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (ring
Propane carbonyl) piperidines -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- first
Oxy-1,2,3,4- naphthane -2- carbonyls) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (oxane -
2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
(6- is fluoro- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
3,4- dihydro -2H-1- chromene -2- carbonyls) -5- Phenylpyrrolidine -2- formic acid；
(ring is amyl- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
3- alkene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
Butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (2,
3- dimethyl phenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (2-
Fluorophenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [2- (Phenylsulfanyl) propiono] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2S) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,2-
Difluoro cyclopropane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3-
Dimethylcyclobutane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- second
Base bytyry) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (3-
Chlorophenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [2- (pyridin-4-yl) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (ring penta
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclopropyl
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3-
Difluoro pentamethylene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- fluorine
Cyclobutane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3-
Difluoro cyclobutane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3-
Dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [trans- -2- cyclo-propane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (oxane -4- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (3- methoxyphenyl)
Pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- aminomethyl phenyl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (4- fluoro-2-methylbenzene base) -2- methoxy
Yl pyridines -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,4- difluorophenyl) -2- methoxyl group
Pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxyl group [3,3 '-two pyridine] -5-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,3- difluorophenyl) -2- methoxyl group
Pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (4- aminomethyl phenyl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxyl group -2 '-methyl [3,3 '-two pyrroles
Pyridine] -5- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (3,6- dihydro -2H- pyrans -4- base) -
2- methoxypyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,5-dihydrofuran -3- base) -2- first
Oxygroup pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxyphenyl) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- [({ 2- methoxyl group -5-
[1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (4-
Fluorophenyl) -5- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (1- tert-butyl -5- cyano -1H- pyrazoles -4- carbonyl) -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (2,
4- difluorophenyl) -5- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (4-
Methoxyphenyl) -5- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- first
Base -5- phenyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [5- second
Base -1- (4- fluorophenyl) -3- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [uncle 1-
Butyl -5- (trifluoromethyl) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (5- first
Base -1- phenyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- second
Base -3,5- dimethyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- first
Base -4,5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (4,5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (5- first
Oxygroup -2,3- dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -
4- methoxyl group -1- methyl -2,3- dihydro -1H- indenes -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(4- is chloro- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
1- methyl -2,3- dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- first
Base -2,3- dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(5- is chloro- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
2,3- dihydro -1H- indenes -1- carbonyls) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (3- phenyl -2,3- dihydro -1- benzofuran -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- hydroxyl
Base -3- methylvaleryl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- hydroxyl
Base -3,4- dimethyl-penten acyl group) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -3-Methoxy Pyridine -2- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [4- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1s,
3R, 5S) -3,5- dimethyl cyclohexane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (4,7,7- trimethyl bicyclics [4.1.0] heptane -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4,4-
Difluorocyclohex alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [trans- -
4- hydroxyl -4- (propyl- 2- alkene -1- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (trans- -
4- ethyl -4- hydroxycyclohexan -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [trans- -
4- hydroxyl -4- (propane -2- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (trans- -
4- hydroxyl -4- propyl cyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (butoxy carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- { [(propyl- 2- alkynes -1- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(amyl
Oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
({ [(1S, 2R, 5S) -5- methyl -2- (propane -2- base) cyclohexyl] oxygroup } carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- { [(butyl- 3- alkene -1- base) oxygroup] carbonyl } -3- tert-butyl -4- { [(5- tert-butyl -2-
Methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (methoxy
Base carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(butyl-
2- alkynes -1- base) oxygroup] carbonyl } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (propoxycarbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- { [(propyl- 2- alkene -1- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,2-
Dimethyl propylene oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2- methoxyl group -2- phenyl acetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(1- methoxycyclohexyl) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
2- (3,4- difluorophenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
(6- methyl -3,4- dihydro -2H-1- chromene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of 7-) -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [2- (4- chlorophenoxy) -3- methylbutyryl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (1- anocy clopropyl) -2- methoxyphenyl] methyl } amino) -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3-
Dimethylcyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- first
Oxygroup -3,4- dihydro -2H-1- chromene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [2- (two rings [2.2.1] heptane -2- base) -5- methoxypyridine -4- base] methyl } ammonia
Base) -3- tert-butyl -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- cyclohexyl -5- methoxypyridine -4-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
({ [5- (2- fluorophenyl) -2- methoxypyridine -3- base] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,4- difluorophenyl) -2- methoxyl group
Pyridin-3-yl] methyl } amino) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,6- Dimethoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [3- methoxyl group -6- (trifluoromethyl) pyridine -
2- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
({ [5- (4- fluoro-2-methylbenzene base) -2- methoxypyridine -3- base] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
({ [2- methoxyl group -5- (4- aminomethyl phenyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- fluorine
Hexamethylene -1- alkene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(6- is chloro- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
2,3- dihydro -1H- indenes -1- carbonyls) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [3- first
Base -2- (2- methylphenoxy) bytyry] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (the fluoro- 4- aminomethyl phenyl of 2-) -5- methoxy
Yl pyridines -4- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- fluorophenyl) -5- methoxypyridine -
4- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- methoxyl group -2- (3- methoxyphenyl)
Pyridin-4-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -3- (2- methoxy propane -
2- yl) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [1- (methoxy)
Cyclopropyl] phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -
2- methoxypyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- { [(2- methoxyl group -5- benzene
Yl pyridines -3- base) methyl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [5- (2- fluorophenyl) -
2- methoxypyridine -3- base] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -5- phenyl -1- [(2R*, 5S*) -5- phenyl butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2- aminomethyl phenyl) acetyl group] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(3,3- dimethylcyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2- aminomethyl phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*, 3aR*, 6aS*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1S*, 3aS*, 6aR*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R) -2- methoxyl group -2- phenyl acetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (5,5- dimethyl butyl oxide link -2- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of 7-) -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- (2- methoxypyridine -3-
Base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -3- (2- methoxyl group
Propane -2- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -3,4- dihydro -2H-1- chromene -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -1- { (4E) -2- [(2E)-but-2-ene -1- base] hex- 4- enoyl- } -3- tert-butyl -4-
{ [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methylcyclopropyl groups)
Pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
5- (trimethyl silyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (6- oxygen
Miscellaneous spiral shell [2.5] octane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (oxa-
Cyclobutane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(3R*) -1- methyl -2- oxo-piperidine -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,5-
Dimethyl -1H- pyrazoles -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- (7- methyl -2,3- dihydro -1- benzofuran -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(4- methoxyl group [1,
1 '-biphenyl] -3- base) methyl] amino } -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(1S*, 3S*) -3- methoxycyclohexyl alkane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(1R*, 3R*) -3- methoxycyclohexyl alkane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(4- methoxyl group [1,
1 '-biphenyl] -3- base) methyl] amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
Oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of (2S*) -7-] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of (2R*) -7-] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
{ (2R*) -2- [(2S*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
{ (2S*) -2- [(2R*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1S*, 3R*) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
[2- (is disliked (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
Alkane -2- base) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [cis- -
4- hydroxyl -4- (trifluoromethyl) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [trans- -
4- hydroxyl -4- (trifluoromethyl) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorine
Phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
{ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl)
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [4- hydroxyl -4- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- (4- phenoxybenzoyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { 4- [(oxane -4- base) oxygroup] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { 4- [(pyridine -2- base) oxygroup] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [4- (trifluoromethoxy) benzoyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4,4-
Difluorocyclohex alkane -1- carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- (3,5- dimethyl cyclohexane -1- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2R*) -2,3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2,3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(1R*, 2R*, 3S*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -
2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R*) -2,3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(2,3- dihydros-Isosorbide-5-Nitrae-benzo dioxin -6- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of 6-) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -4- methoxy pyrimidine -5- base) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(3R*) -3,4- dihydro -1H-2- chromene -3- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(3S*) -3,4- dihydro -1H-2- chromene -3- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2S*) fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of -6-] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -5- [2- (dimethylamino) pyrrole
Pyridine -3- base] -4- { [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] amino } -1- [(1R, 2R) -2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) -5- [2- (dimethylamino) pyrrole
Pyridine -3- base] -4- { [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) pyridin-3-yl] -1- [(2R*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) pyridin-3-yl] -1- [(2S*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- (oxane -2- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(3,3- difluorocyclohex alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- cyclobutyl -3- methoxyl group pyridazine -4- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [3- (3-
Chlorphenyl) oxetanes -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- fluorine
Two rings [1.1.1] pentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [1- (2,2- bis- fluoro- 2H-1, between 3- benzo
Dioxole -5- base) cyclopropyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [2- (4- chlorphenyl) -2- methyl-propyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
5- [2- (dimethylamino) pyridin-3-yl] -3- (2- methoxy propane -2- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrole
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -4- (trifluoro
Methyl) pyridine -2- base] amino } -1- [2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) -5- [2- (dimethylamino) pyrrole
Pyridine -3- base] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -4- (trifluoro
Methyl) pyridine -2- base] amino } -1- [(2S*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(1R*, 2R*, 3R*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(1S*, 2S*, 3S*, 4R*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(1R*, 2R*, 3R*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl
Base] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- [(1S) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -4- (fluoroform
Base) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R,
3S) -3- hydroxycyclohexan -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- [(1S, 3S) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- first
Oxygroup pyridin-3-yl) methyl] amino } -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- fluorophenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- [(1S*, 2R*, 4R*) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethoxy) phenyl] methyl } amino) -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- first
Oxygroup -5- (trifluoromethoxy) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R,
3S) -3- hydroxy-3-methyl hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- [({ 2- first
Oxygroup -5- [(trifluoromethyl) sulfanyl] phenyl } methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- [2- (difluoro-methoxy) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 2- methoxyl group -5- [(trifluoromethyl) sulfanyl] phenyl } methyl) ammonia
Base] -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- first
Oxygroup -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- fluorophenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R, 3R) -3- fluorine hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R,
3R) -3- hydroxy-3-methyl hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 2- methoxyl group -5- [(1S, 3s)-tricyclic [3.3.1.13,7] decane-
1- yl] phenyl } methyl) amino] -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (five fluoro- λ6Sulfanyl) phenyl] methyl } ammonia
Base) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R,
2S, 4S) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3S) -3- hydroxycyclohexan -1- carbonyl] -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- [(2S) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- [(1R, 3R) -3- (trifluoromethoxy) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (fluoroform
Base) phenyl] methyl } amino) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (fluoroform
Oxygroup) phenyl] methyl } amino) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R,
2S, 4S) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) benzene
Base] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(4- methoxyl group [1,
1 '-biphenyl] -3- base) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- methoxynaphthalene -2- base) methyl] amino } -5- phenyl -1- { [(third
Alkane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(trifluoromethoxy) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4R, 5S) -3- tert-butyl -4- { [(3- methoxynaphthalene -2- base) methyl] amino } -5- phenyl -1- { [(third
Alkane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4R, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4R, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
(3- methylbutyryl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5-
[1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethoxy) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(3- methoxynaphthalene -2-
Base) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(6- methoxyl group -2,3-
Dihydro -1H- indenes -5- base) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- first
Base bytyry) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(3- methoxyl group -5,6,
7,8- naphthane -2- bases) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- fluorophenyl) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- { [(propane -2-
Base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S) -
6- methoxyl group -1- methyl -2,3- dihydro -1H- indenes -1- carbonyl] -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -
6- methoxyl group -1- methyl -2,3- dihydro -1H- indenes -1- carbonyl] -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S, 3S) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- (2- methoxyl group pyrrole
Pyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- first
Oxygroup -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -
1- { [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- aminomethyl phenyl) -4- { [6- methyl -4- (three
Methyl fluoride) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(pyrrolidin-1-yl) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
5- (2- aminomethyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -5- (2- methylbenzene
Base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -5- (2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5-
(2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Base phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- [({ 1- [(benzyloxy) carbonyl] piperidines -3- base } methyl) amino] -3- tert-butyl -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- ({ [3- (trifluoro
Methyl) cyclohexyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- aminomethyl phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl pyridine -3- base) -4- ({ [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl pyridine -3- base) -4- ({ [2- methoxyl group -4- (fluoroform
Base) phenyl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl pyridine -3- base) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluoro pentamethylene -1- carbonyl) -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxy-propio] -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- (oxane -4- carbonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- ({ [2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
1- [(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (difluoromethyl) phenyl] -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- (oxane -4- carbonyl
Base) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(2 methoxy quinoline -
3- yl) methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(2 methoxy quinoline -
3- yl) methyl] amino } -1- (oxane -4- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- chlorphenyl) methyl] amino } -1- (cyclopenta acetyl
Base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Cyclopentylacetyl) -4- { [(2- aminomethyl phenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Cyclopentylacetyl) -4- { [(2,4- dichlorophenyl) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [4- (trifluoromethyl)
Pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [5- (trifluoromethyl)
Pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(4- chloropyridine -2- base) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [(6- methoxypyridine -2- base) ammonia
Base] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(3- chlorine-2-hydroxyl phenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 6- [(oxane -4- base) oxygroup]
Pyridine -2- base } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,5- Dimethoxyphenyl) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyphenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,3- Dimethoxyphenyl) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3- methoxyphenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 4- Dimethoxyphenyl of 3-) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4-methoxypyridine -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methoxyl group -4- (fluoroform
Base) pyridine -2- base] (methyl) amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [(2,2- bis- fluoro- 2H-1,3- benzo
Dioxole -5- base) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxypyridine -2- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 4- Dimethoxyphenyl of 5-) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3-Methoxy Pyridine -2- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxy pyrimidine -2- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- oxo -4- (trifluoromethyl) -
1,6- dihydropyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [1- (2- methoxy ethyl) -
1H- imidazoles -2- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxypyridine -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 3- Dimethoxyphenyl of 5-) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (morpholine -4- base) pyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,4- dimethoxypyridin -5-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [1- oxo -4- (trifluoromethyl) -
1λ5Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R)-3- tert-butyl-1- (cyclohexane carbo)-4- { [6- methyl-1-oxo-4- (three
Methyl fluoride) -1 λ5Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- cyclopropyl -5- phenyl -4- { [4- (trifluoromethyl)
Pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -1- [two (propane -2-
Base) carbamoyl] -3- methyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (dimethylamino) -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- [two (propane -2-
Base) carbamoyl] -3- methyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- { [4-
(trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- [two (propane -2-
Base) carbamoyl] -3- methyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2-
Methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridine -3-
Base] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(4- cyanopyridine -2- base) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- { [6-
(trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,2- bis- fluoro- 2H-1,3- benzene
And dioxole -4- base) methyl] amino -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridine -3-
Base] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R) -3- cyclopropyl -1- [two (propane -2- base) carbamoyls] -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -3- cyclopropyl -1- [two
(propane -2- base) carbamoyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (2- methoxyl group ethylsulfonyl) -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (2- methylpropane -2- sulfonyl) -
4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (1- methyl cyclopropane -1- sulphonyl
Base) -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (cyclopropanesulfonyl) -4- { [6-
Methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (ethylsulfonyl) -4- { [6- methyl -
4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (DimethylsuIfamoyl) -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- [ethyl (methyl) sulfamoyl] -
4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (mesyl) -4- { [6- methyl -
4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(4R, 6R, 7R) -5- (cyclohexane carbo) -7- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -
6- phenyl -5- azaspiro [2.4] heptane -4- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -5-
(6- methoxypyridine -2- base) -1- [(1R, 5S, 6S) -3- oxabicyclo [3.1.0] hexane -6- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -1-
[two (propane -2- base) carbamoyls] -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (fluoroform
Base) phenyl] methyl } amino) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- { [6- methyl -4- (three
Methyl fluoride) pyridine -2- base] amino } -1- (3- oxabicyclo [3.1.0] hexane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- { [6- methyl -4- (three
Methyl fluoride) pyridine -2- base] amino } -1- (oxane -2- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- methoxy ethoxy) -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [1- (2- methoxy ethyl) -2-
Oxo -5- (trifluoromethyl) -1,2- dihydropyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- hydroxyl-oxethyl) -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- (oxane -3- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- [(3R*) -3- methyl oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- (3- oxabicyclo [3.1.0] hexane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [the chloro- 5- of 2- (2- methoxy ethoxy) pyridin-4-yl]
Methyl } amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 5- pyridone -4- base of 2-) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- ({ [2- amino -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -3-
Tert-butyl -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -4- { [6- (difluoro-methoxy) pyridine -2- base] amino } -5- (6-
Methoxypyridine -2- base) -1- (3- methyl oxane -3- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -1- (3- methyl oxane -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- hydroxyl -5- (mesyl)
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- methoxy ethoxy) -
5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- cyano-phenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- [the third oxygen of 3- (mesyl)
Base] -5- (trifluoromethyl) phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (3- fluorine propoxyl group) -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- [({ 2- [2- (fluoroform
Oxygroup) ethyoxyl] -5- (trifluoromethyl) phenyl } methyl) amino] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- hydroxyl-oxethyl) -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R*) -2-
Methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2-
Methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2S) -2-
Methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2,4- Dimethoxyphenyl) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(3- methoxyl group [1,1 '-biphenyl] -4- base) methyl] ammonia
Base } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -
4- (trifluoromethyl) pyridine -2- base] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1-
[(cyclobutyl oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (6- methoxypyridine -2- base) -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [(2R) -2- methoxyl group -2- phenyl
Acetyl group] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (dimethyl
Amino) phenyl] -1- [(2R) -2- methoxyl group -2- phenyl acetyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2R) -3,3,3- tri- fluoro- 2- methoxyl group -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2R) -3,3,3- tri- fluoro- 2- methoxyl group -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (4,4- difluorocyclohex alkane -1- carbonyl) -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- phenyl -1- (spiral shell [2.5] octane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- methoxyl group -2- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- fluoro- 2- (mesyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the bromo- 2- cyano-phenyl of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- [(1R, 2S, 4S)-two ring [2.2.1] heptane -2- carbonyl] -3- tert-butyl -
4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- [(the chloro- 3-Methoxy Pyridine -2- base of 5-) amino] -1- (cyclohexane carbo) -
3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [[2- methoxyl group -4- (trifluoromethyl) phenyl] methyl ammonia
Base] -5- phenyl -1- [(2R*) -2- phenylpropionyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Isosorbide-5-Nitrae-dioxanes -2- carbonyl) -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(cyclobutyl oxygroup) carbonyl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene carbonyl
Base) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2R)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(3- methoxyl group -5,5,8,8- tetramethyl -5,
6,7,8- naphthane -2- bases) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- dihydro -2H-1- chromene -6-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- cyano -2- fluorophenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,3- dihydro -1- benzofuran -5- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- fluoro- 2- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ the chloro- 2- of 5- [(propane -2- base) oxygroup] phenyl } methyl) amino] -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- cyano -4- fluorophenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- chloro-4-methoxy phenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- cyano -4- fluorophenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [3- fluoro- 4- (trifluoromethoxy) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- dihydro -2H-1,5- benzo dioxas
Cycloheptene -7- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- dichlorophenyl) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- bromo- 2- (difluoro-methoxy) phenyl] methyl } amino) -3- tert-butyl -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,2- bis- fluoro- 2H-1, dioxy between 3- benzo
Heterocyclic pentene -5- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- Dimethoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- 3,5-dimethylphenyl) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(1- benzofuran -5- base) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- fluoro- 4- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [1- (mesyl) cyclopropane -1- carbonyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [4- (trifluoromethyl) phenyl] first
Base } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoromethyl) phenyl] methyl } ammonia
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(7- chloro- 2H-1,3- benzodioxole -5- base) methyl]
Amino } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- (difluoro-methoxy) -3,5- dimethyl
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- chloro- 2H-1,3- benzodioxole -5- base) methyl]
Amino } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (ring
Hexane carbonyl) -5- (3-Methoxy Pyridine -2- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(4- carbamoyl -6- chloropyridine -2- base) amino] -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 3- cyano -5- fluorine pyridine -2- base of 6-) amino] -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 4- cyanopyridine -2- base of 6-) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [the chloro- 4- of 6- (2- hydroxy propane -2- base) pyridine -2- base] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(3- cyano -4,6- lutidines -2- base) amino] -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 3- ethyl quinolinium -2- base of 7-) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- [(6- anilino--nicotinonitrile -2- base) amino] -3- tert-butyl -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(7- methoxyl group -4- methylquinoline -2- base) ammonia
Base] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(4- ethoxyquinoline -2- base) amino] -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ 5- [(2- oxo pyridine -1 (2H)-yl) first
Base] pyridine -2- base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(7- methoxyl group -3- methylisoquinolinium -1- base)
Amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (t-Butylcarbamoyl) pyridine -2- base] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(isoquinolin -3- base) amino] -5- phenyl pyrazoline
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(1,3- dimethyl -2,4- dioxo -1,2,
3,4- tetrahydropyridines simultaneously [4,3-d] pyrimidine -5- base) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (2- dicyanopropane -2- base) pyridine -2- base] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (1- anocy clopropyl) pyridine -2- base] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [3- (benzyloxy) pyridine -2- base] amino } -3- tert-butyl -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (t-Butylcarbamoyl) pyridin-3-yl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(isoquinolin -4- base) amino] -5- phenyl pyrazoline
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- (pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5R) -3- tert-butyl -5- (3- chloropyridine -2- base) -1- (cyclohexane carbo) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- chlorine
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Base acetyl group) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (butane -2- base) -2- methoxyphenyl] methyl } amino) -3- tert-butyl -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2- ethyl-butyl) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- phenylethyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,4-
Difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,4-
Difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- first
Butylcyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- first
Butylcyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,5-
Dimethyl -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- first
Base -1H- indoles -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(6- is fluoro- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
2H, 4H-1,3- benzo dioxin -8- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [2- (propane -2- base) oxane -4- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- oxyquinoline -3- base) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (morpholine -4- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(S*) -
2- (the chloro- 3- methyl-1 H- pyrazol-1-yl of 4-) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4-
({ [2- methoxyl group -5- (tricyclic [3.3.1.13,7] decane -1- base) phenyl] methyl amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (4- methyl piperazine -1-
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methyl-1 H- pyrrole
Azoles -4- base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (1- cyclopropyl -1H- pyrazoles -4- base) -
2- methoxyphenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- [({ 2- methoxyl group -5-
[(1S, 3S)-tricyclic [3.3.1.13,7] decane -1- base] phenyl methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] first
Base } amino) -3- (1- methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (3,
5- dimethyl phenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (1,2,3,4- naphthane -2- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(1R, 5S)-tricyclic [3.2.1.02,4] octane -3- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [2- (sulphur benzene -2- base) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (3-
Aminomethyl phenyl) -5- (propane -2- base) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- first
Butylcyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,5- dimethyl cyclohexane -1- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- dimethylcyclopentane -1- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
(3- methyl cyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -5- phenyl -1- { (2R, 3R) -3- [(1H- pyrazol-1-yl) methyl] butyl oxide link -2- carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,5- dimethyl cyclohexane -1- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3-
Dimethyl cyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,2-
Dimethylcyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- (2- hexahydrotoluene -1- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) amino) -
1- (3,5- dimethyleyelohexane alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(2- hexahydrotoluene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
Phenyl -1- [3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2R*) fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of -6-] pyrrolidines -2- first
Acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- (cis- -4- hydroxyl -4-
Propyl cyclohexane -1- carbonyl) -4- { [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] amino } -1- [(1S, 2S) -2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] amino } -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
Phenyl -1- [2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2- methoxyl group -2- phenyl acetyl] -2- methyl -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -4- (trifluoro
Methyl) pyridine -2- base] amino } -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [two (third
Alkane -2- base) carbamoyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (difluoro-methoxy) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- { [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- (2- fluorophenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5-
[(3S, 5S)-tricyclic [3.3.1.13,7] decane -1- base] phenyl methyl) amino] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrole
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
[2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5-
[(trifluoromethyl) sulfanyl] phenyl } methyl) amino] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- methoxyl group -5,5,8,8- tetramethyls -5,6,7,8- naphthane -2-
Base) methyl] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
1- (cyclohexane carbo) -5- (1- methyl -2- oxo -1,2- dihydropyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(7S) -
2,2- bis- fluoro- 7- methyl -6,7- dihydro -2H- furans simultaneously [2,3-f] [1,3] benzodioxole -7- carbonyl] -5-
(2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethoxy) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(2- methybutane -2- base) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
5- (2- methoxypyridine -3- base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
5- (2- methoxypyridine -3- base) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- ({ [1- (propane -
2- yl) piperidin-4-yl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -5- (2- chlorphenyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- hydroxyl -5- (methoxycarbonyl) phenyl] methyl } amino) -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
And its pharmaceutically acceptable salt.
Formula (II)
One embodiment is related to the compound with (II),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl and C3-C6Naphthenic base；
R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl；Its
In the R3C1-C6The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-
C6Alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy,
C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And
R3AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；Wherein by R3And R3AAnd attached by them
The C that carbon is formed3-C6The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring
Base, L1-C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring
Base, C3-C11Naphthenic base and C4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, should
Group is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN,
NO2, F, Cl, Br and I；Wherein L1It is not present, or is selected from the group, which is made up of: C1-C6Alkylidene, C2-C6Alkenylene,
C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene and C2-C6Alkynylene, it is single
Solely or as group a part, be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、
SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, the 4- condensed with phenyl group
6 unit monocycle heterocycles, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl and benzene
The condensed 4-6 unit monocycle heterocycle of base group, C3-C11Naphthenic base and C4-C11Cycloalkenyl optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
And C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、
OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces,
The group is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、F、
Cl, Br and I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R9C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23、OH、
Oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl, with
And 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN,
NO2, F, Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
Heterocycle；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
The substituent group that ring group is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I；
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
Another embodiment is related to the compound with formula (II),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl and C3-C6Naphthenic base；
R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl；Its
In the R3C1-C6The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-
C6Alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy,
C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And
R3AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；Wherein by R3And R3AAnd attached by them
The C that carbon is formed3-C6The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6Alkylidene)x-5-11
Unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-C11Naphthenic base and (C1-C6Alkylene
Base)x-C4-C11Cycloalkenyl；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)x-
The 5-11 unit's heteroaryl of 5-11 unit's heteroaryl, (C1-C6Alkylidene)x4-12 circle heterocyclic ring the base, (C of -4-12 circle heterocyclic ring base1-C6Alkylene
Base)x-C3-C11The C of naphthenic base3-C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11The C of cycloalkenyl4-C11Cycloalkenyl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、C(O)
NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and C4-
C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and C4-C11Cycloalkenyl optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R12、OR12、NR13R14, OH, oxo, CN,
NO2, F, Cl, Br and I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
And C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、
OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces,
The group is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、F、
Cl, Br and I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R9C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23、OH、
Oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl, with
And 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN,
NO2, F, Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
Heterocycle；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
The substituent group that ring group is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I；
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl；And
X is 0 or 1.
In one embodiment of formula (II), R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6、
And C (O) NR7R8.In another embodiment of formula (II), R1It is C (O) R6Or C (O) OR6.In another implementation of formula (II)
In example, R1It is SO2R6.In another embodiment of formula (II), R1It is C (O) R6.In another embodiment of formula (II), R1
It is C (O) OR6.In another embodiment of formula (II), R1It is C (O) NR7R8。
In one embodiment of formula (II), R2It is C (O) OH or its bioisostere.In another of formula (II)
In embodiment, R2It is-P (O) (OH)2、-P(O)(OH)(H)、-P(O)(OH)(O-C1-C6Alkyl) ,-P (O) (CH3)(OH)、-B
(OH)2、-SO3H、-CH(OH)CF3、-C(O)NH(OH)、-C(O)NH(CN)、-C(O)NHSO2RG3a、-SO2NHC(O)RG3a、-C
(O)NHSO2NHRG3a、-C(O)NHSO2N(RG3a)2、-SO2NH2、-SO2NHRG3a、-SO2N(RG3a)2、-C(O)NHS(O)(RG3a)=
NC(O)RG3a、-C(O)NHS(O)(RG3a)=NRG3b、
Wherein
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl, C1-C6Halogenated alkyl or
GA；
RG3bIt is hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl or GA；
GAIt is independently naphthenic base, cycloalkenyl, aryl or heteroaryl at each occurrence, is not take each independently
Generation or by 1,2 or 3 R being selected independentlyuWhat group replaced；Wherein
RuIt is independently C at each occurrence1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halogen, C1-C6Halogenated alkyl ,-
CN, oxo ,-NO2、-ORj、-OC(O)Rk、-OC(O)N(Rj)2、-S(O)2Rj、-S(O)2N(Rj)2、-C(O)Rk、-C(O)ORj、-C
(O)N(Rj)2、-N(Rj)2、-N(Rj)C(O)Rk、-N(Rj)S(O)2Rk、-N(Rj)C(O)O(Rk) or-N (Rj)C(O)N(Rj)2；
RjAt each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl or C1-C6Alkyl halide
Base；And
RkAt each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl or C1-C6Halogenated alkyl.?
In another embodiment of formula (II), R2It is-P (O) (OH)2、-P(O)(OH)(H)、-B(OH)2、-SO3H、-CH(OH)CF3、-C
(O)NH(OH)、-C(O)NH(CN)、-C(O)NHSO2RG3a、-SO2NHC(O)RG3a、-C(O)NHSO2NHRG3a、-C(O)NHSO2N
(RG3a)2、-SO2NH2、-SO2NHRG3a、-SO2N(RG3a)2、-C(O)NHS(O)(RG3a)=NC (O) RG3a、-C(O)NHS(O)
(RG3a)=NRG3bOrWherein
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl, C1-C6Halogenated alkyl or
GA；
RG3bIt is hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl or GA；
GAIt is independently naphthenic base, cycloalkenyl, aryl or heteroaryl at each occurrence, is not take each independently
Generation or by 1,2 or 3 R being selected independentlyuWhat group replaced；Wherein
RuIt is independently C at each occurrence1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halogen, C1-C6Halogenated alkyl ,-
CN, oxo ,-NO2、-ORj、-OC(O)Rk、-OC(O)N(Rj)2、-S(O)2Rj、-S(O)2N(Rj)2、-C(O)Rk、-C(O)ORj、-C
(O)N(Rj)2、-N(Rj)2、-N(Rj)C(O)Rk、-N(Rj)S(O)2Rk、-N(Rj)C(O)O(Rk) or-N (Rj)C(O)N(Rj)2；
RjAt each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl or C1-C6Alkyl halide
Base；And
RkAt each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl or C1-C6Halogenated alkyl.
In another embodiment of formula (II), R2It is C (O) OH.In another embodiment of formula (II), R2It is-C (O)
NHSO2RG3aOr-C (O) NHSO2N(RG3a)2；RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkane
Base or GA；Also, GAIndependently naphthenic base at each occurrence, the naphthenic base be independently unsubstituted or by 1,2 or
3 R being selected independentlyuWhat group replaced；Wherein RuIt is independently C at each occurrence1-C6Alkyl.In the another of formula (II)
In a embodiment, R2It is-C (O) NHSO2RG3a；RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6
Alkyl or GA；Also, GAIndependently naphthenic base at each occurrence, the naphthenic base be independently unsubstituted or by 1,2,
Or 3 R being selected independentlyuWhat group replaced；Wherein RuIt is independently C at each occurrence1-C6Alkyl.In the another of formula (II)
In one embodiment, R2It is-C (O) NHSO2N(RG3a)2；And RG3aIt is independently C at each occurrence1-C6Alkyl.
In one embodiment of formula (II), R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6Halogen
Substituted alkyl and C3-C6Naphthenic base.In another embodiment of formula (II), R2AIt is hydrogen or C1-C6Alkyl.In the another of formula (II)
In one embodiment, R2AIt is hydrogen.In another embodiment of formula (II), R2AIt is C1-C6Alkyl.In another reality of formula (II)
It applies in example, R2AIt is CH3。
In one embodiment of formula (II), R2It is C (O) OH；And R2AIt is hydrogen.
In one embodiment of formula (II),
R2It is-P (O) (OH)2、-P(O)(OH)(H)、-B(OH)2、-SO3H、-CH(OH)CF3、-C(O)NH(OH)、-C(O)
NH(CN)、-C(O)NHSO2RG3a、-SO2NHC(O)RG3a、-C(O)NHSO2NHRG3a、-C(O)NHSO2N(RG3a)2、-SO2NH2、-
SO2NHRG3a、-SO2N(RG3a)2、-C(O)NHS(O)(RG3a)=NC (O) RG3a、-C(O)NHS(O)(RG3a)=NRG3bOr
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl, C1-C6Halogenated alkyl or
GA；
RG3bIt is hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl or GA；
GAIt is independently naphthenic base, cycloalkenyl, aryl or heteroaryl at each occurrence, is not take each independently
Generation or by 1,2 or 3 R being selected independentlyuWhat group replaced；Wherein
RuIt is independently C at each occurrence1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, halogen, C1-C6Halogenated alkyl ,-
CN, oxo ,-NO2、-ORj、-OC(O)Rk、-OC(O)N(Rj)2、-S(O)2Rj、-S(O)2N(Rj)2、-C(O)Rk、-C(O)ORj、-C
(O)N(Rj)2、-N(Rj)2、-N(Rj)C(O)Rk、-N(Rj)S(O)2Rk、-N(Rj)C(O)O(Rk) or-N (Rj)C(O)N(Rj)2；
RjAt each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl or C1-C6Alkyl halide
Base；
RkAt each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl or C1-C6Halogenated alkyl；And
And
R2AIt is hydrogen.In one embodiment of formula (II), R2It is-C (O) NHSO2RG3aOr-C (O) NHSO2N(RG3a)2；
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl or GA；
GAIt is independently naphthenic base at each occurrence, the naphthenic base is independently unsubstituted or by 1,2 or 3
The R being selected independentlyuWhat group replaced；
RuIt is independently C at each occurrence1-C6Alkyl；And
R2AIt is hydrogen.
In one embodiment of formula (II), R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base,
Phenyl and 5-6 unit's heteroaryl；The wherein R3C1-C6Alkyl is optionally independently selected by one or more from the substituent group of the following group
Replace, which is made up of: C1-C6Alkoxy, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3C3-C6Naphthenic base,
The substituent group that phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R3AIndependently select
From the following group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl.In another embodiment of formula (II),
R3It is selected from the group, which is made up of: C1-C6Alkyl and C3-C6Naphthenic base；The wherein R3C1-C6Alkyl optionally by one or
Multiple C1-C6Alkoxy replaces；The wherein R3C3-C6Naphthenic base is optionally by one or more C1-C6Alkyl replaces；And R3ASolely
It is on the spot hydrogen.In another embodiment of formula (II), R3It is C1-C6Alkyl；The wherein R3C1-C6Alkyl optionally by one or
Multiple C1-C6Alkoxy replaces；And R3AIt is independently hydrogen.In another embodiment of formula (II), R3It is C3-C6Naphthenic base；
The wherein R3C3-C6Naphthenic base is optionally by one or more C1-C6Alkyl replaces；And R3AIt is hydrogen.In a reality of formula (II)
It applies in example, R3It is CH3, and R3AIt is hydrogen.In one embodiment of formula (II), R3It is C (CH3)3, and R3AIt is hydrogen.In formula
(II) in one embodiment, R3It is C (OCH3)(CH3)2, and R3AIt is hydrogen.In one embodiment of formula (II), R3It is ring
Propyl, the wherein R3Cyclopropyl is optionally by a CH3Replace；And R3AIt is hydrogen.In one embodiment of formula (II), R3It is
Two rings [1.1.1] pentyl, and R3AIt is hydrogen.
In one embodiment of formula (II), R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；Wherein
By R3And R3AAnd C that the carbon attached by them is formed3-C6Naphthenic base is optionally independently selected by one or more from the following group
Substituent group replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2、
F, Cl, Br and I.In another embodiment of formula (II), R3And R3AUnsubstituted C is formed together with the carbon attached by them3-
C6Naphthenic base.In another embodiment of formula (II), R3And R3ACyclopropyl is formed together with the carbon attached by them.
In one embodiment of formula (II), R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1-5-11
Unit's heteroaryl, L1- 4-12 circle heterocyclic ring base, L1-C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4C6-C10Aryl,
5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base, C3-C11Naphthenic base and C4-C11Cycloalkenyl optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si
(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；Wherein L1It is not present, or is selected from the group, the group is by with the following group
At: C1-C6Alkylidene, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-
C6Alkenylene and C2-C6Alkynylene is optionally independently selected by one or more from either individually or as a part of group
The substituent group of the following group replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And R4ABe selected from the group, the group by
Consisting of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl.In another embodiment of formula (II), R4It is L1, it is not present,
Or be selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring base and L1-
C3-C11Naphthenic base；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base and C3-C11Naphthenic base is optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、SR9、
NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is selected from the group, which is made up of: C1-C6Alkylene
Base, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene, with
And C2-C6Alkynylene is optionally independently selected by one or more from the substitution of the following group either individually or as a part of group
Base replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And R4AIt is selected from the group, which is made up of:
Hydrogen and C1-C6Alkyl.In another embodiment of formula (II), R4It is L1-C6-C10Aryl；The wherein R4C6-C10Aryl is optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、SR9、
NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.At formula (II)
Another embodiment in, R4It is L1- 5-11 unit's heteroaryl；The wherein R45-11 unit's heteroaryl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、
SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.In another embodiment of formula (II), R4
It is L1- 4-12 circle heterocyclic ring base；The wherein R44-12 circle heterocyclic ring base is optionally independently selected by one or more from the substituent group of the following group
Replace, which is made up of: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；
Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.In another embodiment of formula (II), R4It is L1-C3-C11Naphthenic base；Its
In the R4L1-C3-C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylene
Base；And R4AIt is hydrogen.In one embodiment of formula (II), R4And R4A4-12 circle heterocyclic ring is formed together with the carbon attached by them
Base；The substituent group that wherein the 4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2、F、Cl、
Br and I.In another embodiment of formula (II), R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Its
In the 4-12 circle heterocyclic ring base be optionally independently selected by one or more from the substituent group of the following group and replace, which is made up of:
OR9And Cl.
In one embodiment of formula (II), R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10
Aryl, (C1-C6Alkylidene)x- 5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-
C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11Cycloalkenyl；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-
C10First aryl, (C1-C6Alkylidene)xThe 5-11 unit's heteroaryl of -5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base
4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-C11The C of naphthenic base3-C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11
The C of cycloalkenyl4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2、F、Cl、Br
And I；R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；And x is 0 or 1.In formula
(II) in another embodiment, R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6
Alkylidene)x- 5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base and (C1-C6Alkylidene)x-C3-C11Cycloalkanes
Base；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)x- 5-11 unit's heteroaryl
5-11 unit's heteroaryl, (C1-C6Alkylidene)xThe 4-12 circle heterocyclic ring base and (C of -4-12 circle heterocyclic ring base1-C6Alkylidene)x-C3-
C11The C of naphthenic base3-C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0
Or 1.In another embodiment of formula (II), R4It is (C1-C6Alkylidene)x-C6-C10Aryl；The wherein R4(C1-C6Alkylidene)x-
C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、
C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0 or 1.
In another embodiment of formula (II), R4It is (C1-C6Alkylidene)x- 5-11 unit's heteroaryl；The wherein R4(C1-C6
Alkylidene)xThe substituent group that -5-11 unit's heteroaryl is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0
Or 1.In another embodiment of formula (II), R4It is (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base；The wherein R4(C1-C6Alkylene
Base)xThe substituent group that -4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of:
R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0 or 1.?
In another embodiment of formula (II), R4It is (C1-C6Alkylidene)x-C3-C11Naphthenic base；The wherein R4(C1-C6Alkylidene)x-C3-
C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C
(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0 or 1.
In one embodiment of formula (II), R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 member are miscellaneous
Aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-C10
First aryl, 5-11 unit's heteroaryl, the 4-6 unit monocycle heterocycle condensed with phenyl group, C3-C11Naphthenic base and C4-C11Cycloalkenyl
The substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14、OH、
Oxo, CN, NO2, F, Cl, Br and I；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl,
C1-C6Halogenated alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
Base and 4-12 circle heterocyclic ring base；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R13And R14Every
Secondary is hydrogen or C each independently when occurring1-C6Alkyl.In another embodiment of formula (II), R5Be selected from the group, the group by with
Lower composition: C6-C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl；The wherein R5C6-
C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl are optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12Occurring every time
When independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 member
Heterocycle；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In another embodiment of formula (II),
R5It is selected from the group, which is made up of: C6-C10First aryl, the 4-6 unit monocycle heterocycle and 5-11 condensed with phenyl group
Unit's heteroaryl；The wherein R5C6-C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14、OH、F、
Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-
C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R12C3-C11Naphthenic base and 4-12 circle heterocyclic ring base optionally by one or
Multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkyl halide
Base, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；And R13And R14Going out every time
It is now C each independently1-C6Alkyl.
In one embodiment of formula (II), R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 member are miscellaneous
Aryl, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base and C4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and I；R12At each occurrence independently selected from the following group, the group
It is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl,
C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl,
C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2、F、
Cl, Br and I；And R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl.In another implementation of formula (II)
In example, R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 unit's heteroaryl；The wherein R5C6-C10First aryl and
The substituent group that 5-11 unit's heteroaryl is optionally independently selected by one or more from the following group replaces, which is made up of: R12、
OR12、NR13R14, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-
C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-
C6Alkyl.In another embodiment of formula (II), R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 member
Heteroaryl；The wherein R5C6-C10First aryl and 5-11 unit's heteroaryl are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: R12、OR12、NR13R14, F, Cl and Br；R12At each occurrence independently selected from the following group,
The group is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；It is wherein each
R12C3-C11The substituent group that naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, the group
It is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R13
And R14It is C each independently at each occurrence1-C6Alkyl.
In another embodiment of formula (II), R5It is C6-C10First aryl；The wherein R5C6-C10First aryl is optionally by one
A or multiple substituent groups independently selected from the group below replace, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Cycloalkanes
Base and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In the another of formula (II)
In one embodiment, R5It is the 4-6 unit monocycle heterocycle condensed with phenyl group；The wherein R5, i.e. the 4-6 condensed with phenyl group
Unit monocycle heterocycle, the substituent group for being optionally independently selected by one or more from the following group replace, which is made up of: R12、
OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl,
C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is each independently at each occurrence
C1-C6Alkyl.In another embodiment of formula (II), R5It is 5-11 unit's heteroaryl；The wherein R55-11 unit's heteroaryl is optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and
Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Ring
Alkyl and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In formula (II)
In another embodiment, R5It is 5-11 unit's heteroaryl；The wherein R55-11 unit's heteroaryl is optionally independently selected by one or more
Replace from the substituent group of the following group, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence solely
It is on the spot selected from the group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring
Base；Wherein each R12C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-
C6Alkyl)2, OH, oxo, CN, NO2, OH, F, Cl, Br and I；And R13And R14It is C each independently at each occurrence1-C6
Alkyl.
In another embodiment of formula (II), R5It is unsubstituted phenyl.In another embodiment of formula (II), R5
It is phenyl；The wherein R5The substituent group that phenyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R12、OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14At each occurrence respectively
It is independently C1-C6Alkyl.In another embodiment of formula (II), R5It is phenyl；The phenyl is by a R12Replace；And R12
It is C1-C6Alkyl.In another embodiment of formula (II), R5It is phenyl；The phenyl is by a R12Replace；And R12It is CH3Or
CH(CH3)2.In another embodiment of formula (II), R5It is pyridyl group；The pyridyl group optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R12、OR12And NR13R14；R12It is independently C1-C6Alkyl；And
And R13And R14It is C each independently at each occurrence1-C6Alkyl.In another embodiment of formula (II), R5It is pyridine
Base；The substituent group that the pyridyl group is optionally independently selected by one or more from the following group replaces, which is made up of: R12、
OR12And NR13R14；R12It is independently CH3Or CH (CH3)2；And R13And R14It is CH each independently at each occurrence3。
In another embodiment of formula (II), R5It is pyridyl group；The wherein R5Pyridyl group is optionally independently selected by one or more from
The substituent group of the following group replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12It is independent at each occurrence
Ground is selected from the group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring
Base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.
In one embodiment of formula (II), R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl,
C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Its
In the R6C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally independently selected by one or more from the substituent group of the following group
Replace, which is made up of: R15、OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、
SO2R18、NR19R20, OH, oxo, CN, NO2, F, Cl, Br and I；R15At each occurrence independently selected from the following group, the group by with
Lower composition: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11
Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Its
In each R156-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy,
C1-C6Halogenated alkyl, oxo, OH, CN, NO2, F, Cl, Br and I；R16And R17It is hydrogen or C each independently at each occurrence1-
C6Alkyl；And R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-
C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein
Each R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11
Cycloalkenyl and 4-12 circle heterocyclic ring base be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I.In the another of formula (II)
In one embodiment, R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R15、OR15、SR15, OH and F；
The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C(O)R18、C(O)
OR18、SO2R18, OH, oxo, CN, F and Cl；R15At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C2-C6Alkenyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
Ring group；Wherein each R156-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one
A or multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；And
And R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl,
5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10First aryl is appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alcoxyl
Base, 5-6 unit's heteroaryl, CN, F and Cl.
In one embodiment of formula (II), R6It is C1-C6Alkyl；The wherein R6C1-C6Alkyl is optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R15、OR15、SR15, OH and F；And R15Each
Independently selected from the following group when appearance, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-
11 unit's heteroaryls, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from
The substituent group of the following group replaces, which is made up of: C1-C6Alkyl, OH, CN, F and Cl.In another implementation of formula (II)
In example, R6It is C1-C6Alkyl；The wherein R6C1-C6Alkyl is by a R15Replace；And R15It is independently 6- at each occurrence
10 yuan of aryl.In another embodiment of formula (II), R6It is C2Alkyl；The wherein R6C2Alkyl is by a R15Replace；And R15
It is independently phenyl at each occurrence.In another embodiment of formula (II), R6It is C1-C6Alkyl；The wherein R6C1-C6Alkane
Base is unsubstituted.In another embodiment of formula (II), R6It is-CH3.In another embodiment of formula (II), R6Be-
CH(CH3)2.In one embodiment of formula (II), R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R18、OR18、C(O)R18、C(O)OR18、
SO2R18, OH, oxo, CN, F and Cl；And R18At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；It is wherein every
A R18C1-C6Alkyl and C6-C10First aryl be optionally independently selected by one or more from the following group substituent group replace, the group by
Consisting of: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl.In another embodiment of formula (II)
In, R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring base is unsubstituted.In another embodiment of formula (II), R6
It is tetrahydrofuran base.In another embodiment of formula (II), R6It is THP trtrahydropyranyl.In one embodiment of formula (II), R6
It is C3-C11Naphthenic base；The wherein R6C3-C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R18、OR18、C(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；And R18?
Independently selected from the following group when occurring every time, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-11 member
Heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10First aryl optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, 5-6
Unit's heteroaryl, CN, F and Cl.In another embodiment of formula (II), R6It is C3-C11Naphthenic base；The wherein R6C3-C11Ring
Alkyl is optionally replaced by one or more F.In another embodiment of formula (II), R6It is C3-C11Naphthenic base；The wherein C3-
C11Naphthenic base is unsubstituted.In another embodiment of formula (II), R6It is cyclohexyl；The wherein R6Cyclohexyl is by two F
Replace.In another embodiment of formula (II), R6It is cyclopenta.In another embodiment of formula (II), R6It is cyclohexyl.
In one embodiment of formula (II), R1It is C (O) OR6；R6It is C1-C6Alkyl；The wherein R6C1-C6Alkyl is optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: R15、OR15、SR15, OH and F；And
And R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-
10 yuan of aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10
First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: C1-C6Alkyl, OH, CN, F and Cl.
In one embodiment of formula (II), R1It is C (O) OR6；And R6It is C1-C6Alkyl；The wherein R6It is unsubstituted
C1-C6Alkyl.
In one embodiment of formula (II), R1It is C (O) R6；R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring
The substituent group that base is optionally independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C(O)R18、
C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；And R18At each occurrence independently selected from the following group, the group by with
Lower composition: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring
Base；Wherein each R18C1-C6Alkyl and C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl.
In one embodiment of formula (II), R1It is C (O) R6；And R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 member
Heterocycle is unsubstituted.
In one embodiment of formula (II), R9At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and
4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)
NR22R23、SO2R21、NR22R23, OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxygen
Generation, CN, NO2, F, Cl, Br and I；R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-
C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
Ring group；Wherein each R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces,
The group is made up of: OH, oxo, CN, NO2, F, Cl, Br and I；R22And R23Be each independently at each occurrence hydrogen or
C1-C6Alkyl；R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；And R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
In another embodiment of formula (II), R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkane
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl is appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: R21、OR21、C(O)OR21、
NR22R23, OH, CN and F；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 member are miscellaneous
The substituent group that ring group is optionally independently selected by one or more from the following group replaces, which is made up of: R24、OR24、CN、F、
And Cl；R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally one or more
CN replaces；R22And R23It is C each independently at each occurrence1-C6Alkyl；And R24At each occurrence independently selected under
Group, the group are made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base.
In one embodiment of formula (II), R10And R11Be each independently selected from the following group at each occurrence, the group by with
Lower composition: hydrogen, C1-C6Alkyl, phenyl and 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy,
C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I.In another embodiment of formula (II), R10And R11Each
The following group is each independently selected from when appearance, which is made up of: hydrogen and 5-6 unit's heteroaryl；Wherein each R10And R115-6 member
Heteroaryl is optionally by one or more C1-C6Alkoxy replaces.
In one embodiment of formula (II), R4It is (C1-C6Alkylidene)x-C6-C10Aryl；The wherein R4(C1-C6Alkylene
Base)x-C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group replaces, which is made up of: R9
And OR9；R4AIt is hydrogen；X is 0 or 1；And R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl
And C3-C11Naphthenic base；Wherein each R9C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Naphthenic base is optional
Ground is by one or more R24Replace；And R24It is independently C at each occurrence1-C6Alkyl.In one embodiment of formula (II)
In, R4It is L1-C6-C10Aryl；The wherein R4C6-C10First aryl is optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: R9And OR9；Wherein L1It is not present or C1-C6Alkylidene；R4AIt is hydrogen；And R9Each
Independently selected from the following group when appearance, which is made up of: C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9C1-C6Alkyl
Optionally replaced by one or more F；Wherein each R9Naphthenic base is optionally by one or more R24Replace；And R24Each
It is independently C when appearance1-C6Alkyl.
In another embodiment of formula (II), R4It is CH2Phenyl；The wherein R4CH2Phenyl is optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence
Independently selected from the following group, which is made up of: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；It is wherein every
A R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optionally by one or more CH3Replace.In the another of formula (II)
In a embodiment, R4It is phenyl；The wherein R4The substituent group that phenyl is optionally independently selected by one or more from the following group replaces,
The group is made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, which is made up of:
CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and two rings
[1.1.1] amyl is optionally by one or more CH3Replace.
In another embodiment of formula (II), R4It is (C1-C6Alkylidene)x- 5-11 unit's heteroaryl；The wherein R4(C1-C6
Alkylidene)xThe substituent group that -5-11 unit's heteroaryl is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9And OR9；R4AIt is hydrogen；X is 0 or 1；And R9At each occurrence independently selected from the following group, which is made up of:
C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Ring
Alkyl is optionally by one or more R24Replace；And R24It is independently C at each occurrence1-C6Alkyl.In the another of formula (II)
In one embodiment, R4It is L1- 5-11 unit's heteroaryl；The wherein R45-11 unit's heteroaryl optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R9And OR9；L1It is not present or C1-C6Alkylidene；R4AIt is hydrogen；R9
At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9C1-
C6Alkyl is optionally replaced by one or more F；Wherein each R9Naphthenic base is optionally by one or more R24Replace；And R24
It is independently C at each occurrence1-C6Alkyl.
In another embodiment of formula (II), R4It is CH2Pyridyl group；The wherein R4CH2Pyridyl group is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: R9And OR9；R4AIt is hydrogen；And R9Going out every time
Now independently selected from the following group, which is made up of: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Its
In each R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optionally by one or more CH3Replace.In formula (II)
In another embodiment, R4It is pyridyl group；The wherein R4Pyridyl group is optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, the group by with
Lower composition: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and
Two rings [1.1.1] amyl is optionally by one or more CH3Replace.In another embodiment of formula (II), R4It is CH2Quinoline
Base；The wherein R4CH2The substituent group that quinolyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, which is made up of: CH3、CF3, cyclopropyl
Base, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optional
Ground is by one or more CH3Replace.
In one embodiment of formula (II), R4It is selected from the group, which is made up of:
Wherein RxIt is selected from the group, which is made up of: CH3And OCH3, and RyIt is selected from the group, the group is by following
Composition: CF3、CH3、C(CH3)3, cyclopropyl, by CH3Substituted cyclobutyl and two rings [1.1.1] amyl；And n is 0 or 1.
One embodiment is related to the compound with (II),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl；
R3It is selected from the group, which is made up of: C1-C6Alkyl and C3-C6Naphthenic base；The wherein R3C1-C6Alkyl is optionally
By one or more C1-C6Alkoxy replaces；The wherein R3C3-C6Naphthenic base is optionally by C1-C6Alkyl replaces；And
R3AIt is hydrogen；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；
R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6Alkylidene)x-5-11
Unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base and (C1-C6Alkylidene)x-C3-C11Naphthenic base；The wherein R4(C1-
C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)xThe 5-11 unit's heteroaryl of -5-11 unit's heteroaryl,
(C1-C6Alkylidene)xThe 4-12 circle heterocyclic ring base and (C of -4-12 circle heterocyclic ring base1-C6Alkylidene)x-C3-C11The C of naphthenic base3-C11
The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)
OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；
R4AIt is hydrogen；
R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 unit's heteroaryl；The wherein R5C6-C10First virtue
The substituent group that base and 5-11 unit's heteroaryl are optionally independently selected by one or more from the following group replaces, which is made up of:
R12、OR12、NR13R14, F, Cl and Br:
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15, OH and F；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12
The substituent group that circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C
(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)OR21、NR22R23, OH, CN and F；Its
In each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R24、OR24, CN, F and Cl；
R10And R11It is each independently selected from the following group at each occurrence, which is made up of: hydrogen and 5-6 unit's heteroaryl；
Wherein each R10And R115-6 unit's heteroaryl is optionally by one or more C1-C6Alkoxy replaces；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；
R13And R14It is C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, 6-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10
First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10Member
The substituent group that aryl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally replaced by CN；
R22And R23It is C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base；And
X is 0 or 1.
One embodiment is related to the compound with (II),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl；
R3It is selected from the group, which is made up of: C1-C6Alkyl and C3-C6Naphthenic base；The wherein R3C1-C6Alkyl is optionally
By one or more C1-C6Alkoxy replaces；The wherein R3C3-C6Naphthenic base is optionally by C1-C6Alkyl replaces；And
R3AIt is hydrogen；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring
Base and L1-C3-C11Naphthenic base；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base and C3-C11Ring
The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)
OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1Be not present, or be selected from the group, the group by with
Lower composition: C1-C6Alkylidene, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylene
Base, C2-C6Alkenylene and C2-C6Alkynylene, either individually or as a part of group, optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: OR9And Cl；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl and condensed with phenyl group
4-6 unit monocycle heterocycle；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl and the 4-6 member list condensed with phenyl group
The substituent group that ring heterocycle is optionally independently selected by one or more from the following group replaces, which is made up of: R12、OR12、
NR13R14, OH, F, Cl and Br；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15, OH and F；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12
The substituent group that circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C
(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)OR21、NR22R23, OH, CN and F；Its
In each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R24、OR24, CN, F and Cl；
R10And R11It is each independently selected from the following group at each occurrence, which is made up of: hydrogen and 5-6 unit's heteroaryl；
Wherein each R10And R115-6 unit's heteroaryl is optionally by one or more C1-C6Alkoxy replaces；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R12C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6It is halogenated
Alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, 6-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10
First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10Member
The substituent group that aryl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally replaced by CN；
R22And R23It is C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
Exemplary compounds with formula (II) include but is not limited to:
Example 4；7；8；9；10；11；12；13；14；15；16；17；18；19；20；21；22；23；24；25；26；27；28；
29；30；31；32；33；34；35；36；37；38；39；40；41；42；43；44；45；46；47；48；49；50；51；52；53；
54；55；56；57；58；59；60；61；62；63；64；65；66；67；68；69；70；71；72；73；74；75；76；77；78；
79；80；81；82；83；84；85；86；87；88；89；90；91；92；93；94；95；96；97；98；99；100；101；102；
103；104；105；106；107；108；109；110；111；112；113；114；115；116；117；118；119；I-20；I-
34；I-39；I-42；I-43；I-44；I-46；I-47；I-48；I-49；I-50；I-51；I-52；I-53；I-54；I-55；I-
56；I-57；I-58；I-59；I-60；I-61；I-62；I-63；I-64；I-65；I-66；I-67；I-68；I-69；I-70；I-
71；I-72；I-73；I-74；I-75；I-76；I-77；I-78；I-79；I-80；I-81；I-82；I-83；I-84；I-85；I-
86；I-87；I-88；I-89；I-90；I-91；I-92；I-93；I-94；I-95；I-96；I-97；I-98；I-99；I-100；I-
101；I-102；I-103；I-104；I-105；I-106；I-107；I-108；I-109；I-110；I-111；I-112；I-113；
I-114；I-115；I-116；I-117；I-118；I-119；I-120；I-121；I-123；I-124；I-125；I-126；I-
127；I-128；I-129；I-130；I-131；I-132；I-133；I-134；I-135；I-136；I-137；I-138；I-139；
I-140；I-141；I-142；I-143；I-144；I-145；I-146；I-147；I-148；I-149；I-150；I-151；I-
152；I-153；I-154；I-155；I-156；I-157；I-158；I-159；I-160；I-161；I-162；I-163；I-164；
I-165；I-166；I-167；I-168；I-169；I-170；I-171；I-172；I-174；I-175；I-176；I-177；I-
178；I-179；I-180；I-181；I-182；I-183；I-184；I-185；I-186；I-187；I-188；I-189；I-190；
I-191；I-192；I-193；I-194；I-195；I-196；I-197；I-198；I-199；I-200；I-201；I-202；I-
204；I-205；I-206；I-207；I-208；I-209；I-210；I-211；I-212；I-213；I-214；I-215；I-216；
I-217；I-218；I-219；I-220；I-221；I-222；I-223；I-224；I-225；I-226；I-227；I-228；I-
229；I-230；I-231；I-232；I-233；I-234；I-235；I-236；I-237；I-238；I-239；I-240；I-241；
I-242；I-243；I-244；I-245；I-246；I-247；I-248；I-249；I-250；I-251；I-252；I-253；I-
254；I-255；I-256；I-257；I-258；I-259；I-260；I-261；I-262；I-263；I-264；I-265；I-266；
I-267；I-268；I-269；I-270；I-271；I-272；I-273；I-274；I-275；I-276；I-277；I-278；I-
279；I-280；I-281；I-282；I-283；I-284；I-285；I-286；I-287；I-288；I-289；I-290；I-291；
I-292；I-293；I-294；I-295；I-296；I-297；I-298；I-299；I-300；I-301；I-302；I-303；I-
304；I-305；I-306；I-307；I-308；I-309；I-310；II-54；II-62；II-63；II-65；II-81；II-83；
II-84；II-87；II-91；II-92；II-93；II-94；II-95；II-96；II-97；II-98；II-99；II-100；II-
101；II-102；II-103；II-104；II-105；II-106；II-107；II-108；II-109；II-110；II-111；II-
112；II-113；II-114；II-115；II-116；II-117；II-118；II-119；II-120；II-121；II-122；II-
123；II-124；II-125；II-126；II-127；II-128；II-129；II-130；II-131；II-132；II-133；II-
134；II-135；II-136；II-137；II-138；II-139；II-140；II-141；II-144；II-145；II-146；II-
147；II-148；II-149；II-150；II-152；II-153；II-154；II-155；II-156；II-157；II-158；II-
159；II-160；II-161；II-162；II-163；II-164；II-165；II-166；II-167；II-168；II-169；II-
170；II-171；II-172；II-173；II-174；II-175；II-176；II-177；II-178；II-179；II-180；II-
181；II-182；II-183；II-184；II-185；II-186；II-187；II-188；II-189；II-190；II-191；II-
192；II-193；II-194；II-195；II-196；II-197；II-198；II-199；II-200；II-201；II-202；II-
203；II-204；II-205；II-206；II-207；II-208；II-209；II-210；II-211；II-212；II-213；II-
214；II-215；II-216；II-217；II-218；II-219；II-220；II-221；II-222；II-223；II-224；II-
225；II-226；II-227；II-228；II-229；II-230；II-231；II-232；II-233；II-234；II-235；II-
236；II-237；II-238；II-239；II-240；II-241；II-242；II-243；II-244；II-245；II-246；II-
247；II-248；II-249；II-250；II-251；II-252；II-253；II-254；II-255；II-256；II-257；II-
258；II-259；II-260；II-261；II-262；II-263；II-264；II-265；II-266；II-267；II-268；II-
269；II-270；II-271；II-272；II-273；II-274；II-275；II-276；II-277；II-278；II-279；II-
280；II-281；II-282；II-283；II-284；II-285；II-286；II-287；II-288；II-289；II-290；II-
291；II-292；II-293；II-294；II-295；II-296；II-297；II-298；II-299；II-300；II-301；II-
302；II-303；II-304；II-305；II-306；II-307；II-308；II-309；II-310；II-311；II-312；II-
313；II-314；II-315；II-316；II-317；II-318；II-319；II-320；II-321；II-322；II-323；II-
324；II-325；II-326；II-327；II-328；II-329；II-330；II-331；II-332；II-333；II-334；II-
335；II-336；II-337；II-339；II-340；II-341；II-342；II-343；II-344；II-345；II-346；II-
347；II-348；II-349；II-350；II-351；II-352；II-353；II-354；II-355；II-356；II-357；II-
358；II-359；II-360；II-361；II-362；II-363；II-364；II-365；II-366；II-367；II-368；II-
369；II-370；II-371；II-372；II-373；II-374；II-375；II-376；II-377；II-378；II-379；II-
380；II-381；II-382；II-383；II-384；II-385；II-386；II-387；II-388；II-389；II-390；II-
391；II-392；II-394；II-396；II-397；II-398；II-399；II-400；II-401；II-402；II-403；II-
404；II-405；II-406；II-407；II-408；II-409；II-410；II-411；II-414；II-415；II-416；II-
417；II-418；II-419；II-420；II-421；II-422；II-423；II-424；II-425；II-426；II-427；II-
428；II-429；II-430；II-431；II-432；II-433；II-434；II-435；II-436；II-437；II-438；II-
439；II-440；II-441；II-442；II-443；II-444；II-445；II-446；II-447；II-448；II-449；II-
450；II-451；II-452；II-453；II-454；II-455；II-456；II-457；II-458；II-459；II-460；II-
461；II-462；II-463；II-464；II-465；II-466；II-467；II-468；II-469；II-470；II-471；II-
472；II-473；II-474；II-475；II-476；II-477；II-478；II-479；II-480；II-481；II-482；II-
483；II-484；II-485；II-486；II-487；II-488；II-489；II-490；II-491；II-492；II-493；II-
494；II-495；II-496；II-497；II-498；II-499；II-500；II-501；II-502；II-503；II-504；II-
505；II-506；II-507；II-508；II-509；II-510；II-511；II-512；II-513；II-514；II-515；II-
516；II-517；II-518；II-519；II-520；II-521；II-522；II-523；II-524；II-525；II-526；II-
527；II-528；II-529；II-530；II-531；II-532；II-533；II-534；II-535；II-536；II-537；II-
538；II-539；II-540；II-541；II-542；II-543；II-544；II-545；II-546；II-547；II-548；II-
549；II-550；II-551；II-552；II-553；II-557；II-558；II-559；II-560；II-561；II-562；II-
563；II-564；II-565；II-566；II-567；II-568；II-569；II-570；II-571；II-572；II-573；II-
574；II-575；II-576；II-577；II-578；II-579；II-580；II-581；II-582；II-583；II-584；II-
585；II-586；II-587；II-588；II-589；II-590；II-591；II-592；II-593；II-594；II-595；II-
596；II-597；II-598；II-599；II-600；III-78；III-100；III-103；III-118；III-119；III-
120；III-121；III-122；III-123；III-124；III-125；III-126；III-127；III-128；III-129；
III-130；III-131；III-132；III-133；III-134；III-135；III-136；III-137；III-138；III-
139；III-140；III-141；III-142；III-144；III-145；III-146；III-147；III-148；III-149；
III-150；III-151；III-152；III-153；III-154；III-155；III-156；III-157；III-158；III-
159；III-160；III-161；III-162；III-163；III-164；III-166；III-167；III-168；III-169；
III-170；III-171；III-172；III-173；III-174；III-175；III-176；III-177；III-178；III-
179；III-180；III-181；III-182；III-183；III-184；III-185；III-186；III-187；III-188；
III-189；III-190；III-191；III-192；III-193；III-194；III-195；III-196；III-197；III-
198；III-200；III-201；III-202；III-203；III-204；III-205；III-206；III-207；III-208；
III-209；III-210；III-211；III-212；III-213；III-214；III-215；III-216；III-217；III-
218；III-219；III-220；III-221；III-222；III-223；III-224；III-225；III-226；III-227；
III-228；III-229；III-230；III-231；III-232；III-233；III-234；III-235；III-237；And
Its pharmaceutically acceptable salt.
Formula (III)
One embodiment is related to the compound with (III),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring
Base, L1-C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring
Base, C3-C11Naphthenic base and C4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, should
Group is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN,
NO2, F, Cl, Br and I；Wherein L1It is not present, or is selected from the group, which is made up of: C1-C6Alkylidene, C2-C6Alkenylene,
C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene and C2-C6Alkynylene, it is single
Solely or as group a part, be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、
SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, the 4- condensed with phenyl group
6 unit monocycle heterocycles, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl and benzene
The condensed 4-6 unit monocycle heterocycle of base group, C3-C11Naphthenic base and C4-C11Cycloalkenyl optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
And C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、
OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces,
The group is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、F、
Cl, Br and I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R9C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23、OH、
Oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl, with
And 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN,
NO2, F, Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
Heterocycle；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
The substituent group that ring group is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I；
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
Another embodiment is related to the compound with (III),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6Alkylidene)x-5-11
Unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-C11Naphthenic base and (C1-C6Alkylene
Base)x-C4-C11Cycloalkenyl；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)x-
The 5-11 unit's heteroaryl of 5-11 unit's heteroaryl, (C1-C6Alkylidene)x4-12 circle heterocyclic ring the base, (C of -4-12 circle heterocyclic ring base1-C6Alkylene
Base)x-C3-C11The C of naphthenic base3-C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11The C of cycloalkenyl4-C11Cycloalkenyl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、C(O)
NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and C4-
C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and C4-C11Cycloalkenyl optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R12、OR12、NR13R14, OH, oxo, CN,
NO2, F, Cl, Br and I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
And C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、
OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces,
The group is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、F、
Cl, Br and I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R9C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23、OH、
Oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl, with
And 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from down
The substituent group of group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN,
NO2, F, Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member
Heterocycle；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
The substituent group that ring group is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynes
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I；
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl；And
X is 0 or 1.
In one embodiment of formula (III), R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6、
And C (O) NR7R8.In another embodiment of formula (III), R1It is C (O) R6Or C (O) OR6.In another reality of formula (III)
It applies in example, R1It is SO2R6.In another embodiment of formula (III), R1It is C (O) R6.In another embodiment of formula (III)
In, R1It is C (O) OR6.In another embodiment of formula (III), R1It is C (O) NR7R8。
In one embodiment of formula (III), R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1-5-11
Unit's heteroaryl, L1- 4-12 circle heterocyclic ring base, L1-C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4C6-C10Aryl,
5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base, C3-C11Naphthenic base and C4-C11Cycloalkenyl optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si
(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；Wherein L1It is not present, or is selected from the group, the group is by with the following group
At: C1-C6Alkylidene, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-
C6Alkenylene and C2-C6Alkynylene is optionally independently selected by one or more from either individually or as a part of group
The substituent group of the following group replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And R4ABe selected from the group, the group by
Consisting of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl.In another embodiment of formula (III), R4It is L1, do not deposit
, or be selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring base and
L1-C3-C11Naphthenic base；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base and C3-C11Naphthenic base is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、SR9、
NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is selected from the group, which is made up of: C1-C6Alkylene
Base, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene, with
And C2-C6Alkynylene is optionally independently selected by one or more from the substitution of the following group either individually or as a part of group
Base replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And R4AIt is selected from the group, which is made up of:
Hydrogen and C1-C6Alkyl.In another embodiment of formula (III), R4It is L1-C6-C10Aryl；The wherein R4C6-C10Aryl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)OR9、SR9、
NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.At formula (III)
Another embodiment in, R4It is L1- 5-11 unit's heteroaryl；The wherein R45-11 unit's heteroaryl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、
SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.In another embodiment of formula (III),
R4It is L1- 4-12 circle heterocyclic ring base；The wherein R44-12 circle heterocyclic ring base is optionally independently selected by one or more from the substitution of the following group
Base replaces, which is made up of: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and
Br；Wherein L1It is C1-C6Alkylidene；And R4AIt is hydrogen.In another embodiment of formula (III), R4It is L1-C3-C11Cycloalkanes
Base；The wherein R4L1-C3-C11Naphthenic base be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1It is C1-C6It is sub-
Alkyl；And R4AIt is hydrogen.In one embodiment of formula (III), R4And R4A4-12 member is formed together with the carbon attached by them
Heterocycle；Wherein the 4-12 circle heterocyclic ring base be optionally independently selected by one or more from the following group substituent group replace, the group by
Consisting of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2、F、
Cl, Br and I.In another embodiment of formula (III), R4And R4A4-12 circle heterocyclic ring is formed together with the carbon attached by them
Base；The substituent group that wherein the 4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: OR9And Cl.
In one embodiment of formula (III), R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10
Aryl, (C1-C6Alkylidene)x- 5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-
C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11Cycloalkenyl；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-
C10First aryl, (C1-C6Alkylidene)xThe 5-11 unit's heteroaryl of -5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base
4-12 circle heterocyclic ring base, (C1-C6Alkylidene)x-C3-C11The C of naphthenic base3-C11Naphthenic base and (C1-C6Alkylidene)x-C4-C11
The C of cycloalkenyl4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2、F、Cl、Br
And I；R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；And x is 0 or 1.In formula
(III) in another embodiment, R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6
Alkylidene)x- 5-11 unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base and (C1-C6Alkylidene)x-C3-C11Cycloalkanes
Base；The wherein R4(C1-C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)x- 5-11 unit's heteroaryl
5-11 unit's heteroaryl, (C1-C6Alkylidene)xThe 4-12 circle heterocyclic ring base and (C of -4-12 circle heterocyclic ring base1-C6Alkylidene)x-C3-
C11The C of naphthenic base3-C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0
Or 1.In another embodiment of formula (III), R4It is (C1-C6Alkylidene)x-C6-C10Aryl；The wherein R4(C1-C6Alkylene
Base)x-C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group replaces, which is made up of:
R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0 or 1.
In another embodiment of formula (III), R4It is (C1-C6Alkylidene)x- 5-11 unit's heteroaryl；The wherein R4(C1-
C6Alkylidene)xThe substituent group that -5-11 unit's heteroaryl is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0
Or 1.In another embodiment of formula (III), R4It is (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base；The wherein R4(C1-C6It is sub-
Alkyl)xThe substituent group that -4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x be 0 or
1.In another embodiment of formula (III), R4It is (C1-C6Alkylidene)x-C3-C11Naphthenic base；The wherein R4(C1-C6Alkylene
Base)x-C3-C11The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of:
R9、OR9、C(O)OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；R4AIt is hydrogen；And x is 0 or 1.
In one embodiment of formula (III), R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 member
Heteroaryl, the 4-6 unit monocycle heterocycle condensed with phenyl group, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-
C10First aryl, 5-11 unit's heteroaryl, the 4-6 unit monocycle heterocycle condensed with phenyl group, C3-C11Naphthenic base and C4-C11Cyclenes
The substituent group that base is optionally independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14、
OH, oxo, CN, NO2, F, Cl, Br and I；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkane
Base, C1-C6Halogenated alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11
Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Ring
The substituent group that alkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R13And R14?
It is hydrogen or C each independently when occurring every time1-C6Alkyl.In another embodiment of formula (III), R5It is selected from the group, the group
It is made up of: C6-C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group, 5-11 unit's heteroaryl；The wherein R5C6-
C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl are optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12Occurring every time
When independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 member
Heterocycle；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In another embodiment of formula (III),
R5It is selected from the group, which is made up of: C6-C10First aryl, the 4-6 unit monocycle heterocycle and 5-11 condensed with phenyl group
Unit's heteroaryl；The wherein R5C6-C10First aryl, the 4-6 unit monocycle heterocycle condensed with phenyl group and 5-11 unit's heteroaryl are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14、OH、F、
Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-
C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R12C3-C11Naphthenic base and 4-12 circle heterocyclic ring base optionally by one or
Multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkyl halide
Base, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；And R13And R14Going out every time
It is now C each independently1-C6Alkyl.
In one embodiment of formula (III), R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 member
Heteroaryl, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base and C4-C11The substituent group that cycloalkenyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and I；R12At each occurrence independently selected from the following group, the group
It is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl,
C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R126-10 member aryl, 5-11 unit's heteroaryl,
C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2、F、
Cl, Br and I；And R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl.In another reality of formula (III)
It applies in example, R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 unit's heteroaryl；The wherein R5C6-C10First aryl
The substituent group for being optionally independently selected by one or more from the following group with 5-11 unit's heteroaryl replaces, which is made up of: R12、
OR12、NR13R14, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-
C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-
C6Alkyl.In another embodiment of formula (III), R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 member
Heteroaryl；The wherein R5C6-C10First aryl and 5-11 unit's heteroaryl are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: R12、OR12、NR13R14, F, Cl and Br；R12At each occurrence independently selected from the following group,
The group is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；It is wherein each
R12C3-C11The substituent group that naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, the group
It is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And R13
And R14It is C each independently at each occurrence1-C6Alkyl.
In another embodiment of formula (III), R5It is C6-C10First aryl；The wherein R5C6-C10First aryl optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: R12、OR12、NR13R14, OH, F, Cl and
Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Ring
Alkyl and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In formula (III)
In another embodiment, R5It is the 4-6 unit monocycle heterocycle condensed with phenyl group；The wherein R5, i.e. the 4- condensed with phenyl group
6 unit monocycle heterocycles, the substituent group for being optionally independently selected by one or more from the following group replace, which is made up of: R12、
OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl,
C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is each independently at each occurrence
C1-C6Alkyl.In another embodiment of formula (III), R5It is 5-11 unit's heteroaryl；The wherein R55-11 unit's heteroaryl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R12、OR12、NR13R14、OH、F、Cl
And Br；R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11
Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.At formula (III)
Another embodiment in, R5It is 5-11 unit's heteroaryl；The wherein R55-11 unit's heteroaryl optionally by it is one or more independently
Substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence
Independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 member are miscellaneous
Ring group；Wherein each R12C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N
(C1-C6Alkyl)2, OH, oxo, CN, NO2, OH, F, Cl, Br and I；And R13And R14It is each independently at each occurrence
C1-C6Alkyl.
In another embodiment of formula (III), R5It is unsubstituted phenyl.In another embodiment of formula (III),
R5It is phenyl；The wherein R5The substituent group that phenyl is optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: R12、OR12、NR13R14, OH, F, Cl and Br；R12At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；And R13And R14At each occurrence respectively
It is independently C1-C6Alkyl.In another embodiment of formula (III), R5It is phenyl；The phenyl is by a R12Replace；And
R12It is C1-C6Alkyl.In another embodiment of formula (III), R5It is phenyl；The phenyl is by a R12Replace；And R12It is
CH3Or CH (CH3)2.In another embodiment of formula (III), R5It is pyridyl group；The pyridyl group is optionally one or more
Substituent group independently selected from the group below replaces, which is made up of: R12、OR12And NR13R14；R12It is independently C1-C6Alkane
Base；And R13And R14It is C each independently at each occurrence1-C6Alkyl.In another embodiment of formula (III), R5It is
Pyridyl group；The substituent group that the pyridyl group is optionally independently selected by one or more from the following group replaces, which is made up of:
R12、OR12And NR13R14；R12It is independently CH3Or CH (CH3)2；And R13And R14It is each independently at each occurrence
CH3.In another embodiment of formula (III), R5It is pyridyl group；The wherein R5Pyridyl group is optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R12、OR12、NR13R14, OH, F, Cl and Br；R12Occurring every time
When independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11Naphthenic base and 4-12 member
Heterocycle；And R13And R14It is C each independently at each occurrence1-C6Alkyl.
In one embodiment of formula (III), R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl,
C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Its
In the R6C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally independently selected by one or more from the substituent group of the following group
Replace, which is made up of: R15、OR15、SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、
SO2R18、NR19R20, OH, oxo, CN, NO2, F, Cl, Br and I；R15At each occurrence independently selected from the following group, the group by with
Lower composition: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11
Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Its
In each R156-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy,
C1-C6Halogenated alkyl, oxo, OH, CN, NO2, F, Cl, Br and I；R16And R17It is hydrogen or C each independently at each occurrence1-
C6Alkyl；And R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-
C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein
Each R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11
Cycloalkenyl and 4-12 circle heterocyclic ring base be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I.In formula (III)
In another embodiment, R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R15、OR15、SR15, OH and F；
The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C(O)R18、C(O)
OR18、SO2R18, OH, oxo, CN, F and Cl；R15At each occurrence independently selected from the following group, which is made up of: C1-
C6Alkyl, C2-C6Alkenyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
Ring group；Wherein each R156-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one
A or multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；And
And R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl,
5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10First aryl is appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alcoxyl
Base, 5-6 unit's heteroaryl, CN, F and Cl.
In one embodiment of formula (III), R6It is C1-C6Alkyl；The wherein R6C1-C6Alkyl is optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R15、OR15、SR15, OH and F；And R15Each
Independently selected from the following group when appearance, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-
11 unit's heteroaryls, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from
The substituent group of the following group replaces, which is made up of: C1-C6Alkyl, OH, CN, F and Cl.In another implementation of formula (III)
In example, R6It is C1-C6Alkyl；The wherein R6C1-C6Alkyl is by a R15Replace；And R15It is independently 6- at each occurrence
10 yuan of aryl.In another embodiment of formula (III), R6It is C2Alkyl；The wherein R6C2Alkyl is by a R15Replace；And
R15It is independently phenyl at each occurrence.In another embodiment of formula (III), R6It is C1-C6Alkyl；The wherein R6C1-
C6Alkyl is unsubstituted.In another embodiment of formula (III), R6It is-CH3.In another embodiment of formula (III),
R6It is-CH (CH3)2.In one embodiment of formula (III), R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring base is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C(O)R18、C(O)
OR18、SO2R18, OH, oxo, CN, F and Cl；And R18At each occurrence independently selected from the following group, the group is by with the following group
At: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；
Wherein each R18C1-C6Alkyl and C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group replaces,
The group is made up of: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl.In another of formula (III)
In embodiment, R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring base is unsubstituted.In another implementation of formula (III)
In example, R6It is tetrahydrofuran base.In another embodiment of formula (III), R6It is THP trtrahydropyranyl.In a reality of formula (III)
It applies in example, R6It is C3-C11Naphthenic base；The wherein R6C3-C11Naphthenic base is optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: R18、OR18、C(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；And
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-
11 unit's heteroaryls, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10First aryl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy,
5-6 unit's heteroaryl, CN, F and Cl.In another embodiment of formula (III), R6It is C3-C11Naphthenic base；The wherein R6C3-
C11Naphthenic base is optionally replaced by one or more F.In another embodiment of formula (III), R6It is C3-C11Naphthenic base；Its
In the C3-C11Naphthenic base is unsubstituted.In another embodiment of formula (III), R6It is cyclohexyl；The wherein R6Cyclohexyl
Replaced by two F.In another embodiment of formula (III), R6It is cyclopenta.In another embodiment of formula (III), R6
It is cyclohexyl.
In one embodiment of formula (III), R1It is C (O) OR6；R6It is C1-C6Alkyl；The wherein R6C1-C6Alkyl is optional
The substituent group that ground is independently selected by one or more from the following group replaces, which is made up of: R15、OR15、SR15, OH and F；
And R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-
10 yuan of aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base optionally by one or
Multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl.
In one embodiment of formula (III), R1It is C (O) OR6；And R6It is C1-C6Alkyl；The wherein R6It is unsubstituted
C1-C6Alkyl.
In one embodiment of formula (III), R1It is C (O) R6；R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 circle heterocyclic ring
The substituent group that base is optionally independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C(O)R18、
C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；And R18At each occurrence independently selected from the following group, the group by with
Lower composition: C1-C6Alkyl, C2-C6Alkenyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring
Base；Wherein each R18C1-C6Alkyl and C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl.
In one embodiment of formula (III), R1It is C (O) R6；And R6It is 4-12 circle heterocyclic ring base；The wherein R64-12 member
Heterocycle is unsubstituted.
In one embodiment of formula (III), R9At each occurrence independently selected from the following group, which is made up of:
C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl,
And 4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl, C2-C6Alkenyl and C2-C6Alkynyl is optionally one or more
Substituent group independently selected from the group below replaces, which is made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C
(O)NR22R23、SO2R21、NR22R23, OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 member are miscellaneous
Aryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replace, which is made up of: R24、OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxygen
Generation, CN, NO2, F, Cl, Br and I；R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-
C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 member are miscellaneous
Ring group；Wherein each R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Cycloalkanes
Base, C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces,
The group is made up of: OH, oxo, CN, NO2, F, Cl, Br and I；R22And R23Be each independently at each occurrence hydrogen or
C1-C6Alkyl；R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；And R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
In another embodiment of formula (III), R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkane
Base, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl is appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: R21、OR21、C(O)OR21、
NR22R23, OH, CN and F；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 member are miscellaneous
The substituent group that ring group is optionally independently selected by one or more from the following group replaces, which is made up of: R24、OR24、CN、F、
And Cl；R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally one or more
CN replaces；R22And R23It is C each independently at each occurrence1-C6Alkyl；And R24At each occurrence independently selected under
Group, the group are made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base.
In one embodiment of formula (III), R10And R11Be each independently selected from the following group at each occurrence, the group by
Consisting of: hydrogen, C1-C6Alkyl, phenyl and 5-6 unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alcoxyl
Base, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I.In another embodiment of formula (III), R10And R11?
It is each independently selected from the following group when occurring every time, which is made up of: hydrogen and 5-6 unit's heteroaryl；Wherein each R10And R115-
6 unit's heteroaryls are optionally by one or more C1-C6Alkoxy replaces.
In one embodiment of formula (III), R4It is (C1-C6Alkylidene)x-C6-C10Aryl；The wherein R4(C1-C6Alkylene
Base)x-C6-C10The substituent group that first aryl is optionally independently selected by one or more from the following group replaces, which is made up of: R9
And OR9；R4AIt is hydrogen；X is 0 or 1；And R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl
And C3-C11Naphthenic base；Wherein each R9C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Naphthenic base is optional
Ground is by one or more R24Replace；And R24It is independently C at each occurrence1-C6Alkyl.In an implementation of formula (III)
In example, R4It is L1-C6-C10Aryl；The wherein R4C6-C10First aryl is optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: R9And OR9；Wherein L1It is not present or C1-C6Alkylidene；R4AIt is hydrogen；And R9Every
It is secondary when occurring independently selected from the following group, which is made up of: C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9C1-C6Alkane
Base is optionally replaced by one or more F；Wherein each R9Naphthenic base is optionally by one or more R24Replace；And R24Every
Secondary is independently C when occurring1-C6Alkyl.
In another embodiment of formula (III), R4It is CH2Phenyl；The wherein R4CH2Phenyl optionally by one or
Multiple substituent groups independently selected from the group below replace, which is made up of: R9And OR9；R4AIt is hydrogen；And R9Occurring every time
When independently selected from the following group, which is made up of: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein
Each R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optionally by one or more CH3Replace.In the another of formula (III)
In one embodiment, R4It is phenyl；The wherein R4The substituent group that phenyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, the group is by with the following group
At: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and two rings
[1.1.1] amyl is optionally by one or more CH3Replace.
In another embodiment of formula (III), R4It is (C1-C6Alkylidene)x- 5-11 unit's heteroaryl；The wherein R4(C1-
C6Alkylidene)xThe substituent group that -5-11 unit's heteroaryl is optionally independently selected by one or more from the following group replaces, and the group is by following
Composition: R9And OR9；R4AIt is hydrogen；xIt is 0 or 1；And R9At each occurrence independently selected from the following group, which is made up of:
C1-C6Alkyl and C3-C11Naphthenic base；Wherein each R9C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Ring
Alkyl is optionally by one or more R24Replace；And R24It is independently C at each occurrence1-C6Alkyl.In formula (III)
In another embodiment, R4It is L1- 5-11 unit's heteroaryl；The wherein R45-11 unit's heteroaryl is optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: R9And OR9；L1It is not present or C1-C6Alkylidene；R4AIt is hydrogen；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl and C3-C11Naphthenic base；It is wherein each
R9C1-C6Alkyl is optionally replaced by one or more F；Wherein each R9Naphthenic base is optionally by one or more R24Replace；And
And R24It is independently C at each occurrence1-C6Alkyl.
In another embodiment of formula (III), R4It is CH2Pyridyl group；The wherein R4CH2Pyridyl group is optionally by one
A or multiple substituent groups independently selected from the group below replace, which is made up of: R9And OR9；R4AIt is hydrogen；And R9Each
Independently selected from the following group when appearance, which is made up of: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；
Wherein each R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl are optionally by one or more CH3Replace.At formula (III)
Another embodiment in, R4It is pyridyl group；The wherein R4Pyridyl group is optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, the group by
Consisting of: CH3、CF3, cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl, with
And two ring [1.1.1] amyl optionally by one or more CH3Replace.In another embodiment of formula (III), R4It is CH2-
Quinolyl；The wherein R4CH2Quinolyl be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: R9And OR9；R4AIt is hydrogen；And R9At each occurrence independently selected from the following group, which is made up of: CH3、CF3、
Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl；Wherein each R9Cyclopropyl, cyclobutyl and two rings [1.1.1] amyl
Optionally by one or more CH3Replace.
In one embodiment of formula (III), R4It is selected from the group, which is made up of:
Wherein RxIt is selected from the group, which is made up of: CH3And OCH3, and RyIt is selected from the group, the group is by following
Composition: CF3、CH3、C(CH3)3, cyclopropyl, by CH3Substituted cyclobutyl and two rings [1.1.1] amyl；And n is 0 or 1.
One embodiment is related to the compound with (III),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R4It is selected from the group, which is made up of: (C1-C6Alkylidene)x-C6-C10Aryl, (C1-C6Alkylidene)x-5-11
Unit's heteroaryl, (C1-C6Alkylidene)x- 4-12 circle heterocyclic ring base and (C1-C6Alkylidene)x-C3-C11Naphthenic base；The wherein R4(C1-
C6Alkylidene)x-C6-C10The C of first aryl6-C10First aryl, (C1-C6Alkylidene)xThe 5-11 unit's heteroaryl of -5-11 unit's heteroaryl,
(C1-C6Alkylidene)xThe 4-12 circle heterocyclic ring base and (C of -4-12 circle heterocyclic ring base1-C6Alkylidene)x-C3-C11The C of naphthenic base3-C11
The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)
OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br:
R4AIt is hydrogen；
R5It is selected from the group, which is made up of: C6-C10First aryl and 5-11 unit's heteroaryl；The wherein R5C6-C10First virtue
The substituent group that base and 5-11 unit's heteroaryl are optionally independently selected by one or more from the following group replaces, which is made up of:
R12、OR12、NR13R14, F, Cl and Br；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15, OH and F；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12
The substituent group that circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C
(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)OR21、NR22R23, OH, CN and F；Its
In each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R24、OR24, CN, F and Cl；
R10And R11It is each independently selected from the following group at each occurrence, which is made up of: hydrogen and 5-6 unit's heteroaryl；
Wherein each R10And R115-6 unit's heteroaryl is optionally by one or more C1-C6Alkoxy replaces；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；
R13And R14It is C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, 6-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10
First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10Member
The substituent group that aryl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally replaced by CN；
R22And R23It is C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base；And
X is 0 or 1.
One embodiment is related to the compound with (III),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring
Base and L1-C3-C11Naphthenic base；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base and C3-C11Ring
The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of: R9、OR9、C(O)
OR9、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, CN, F, Cl and Br；Wherein L1Be not present, or be selected from the group, the group by with
Lower composition: C1-C6Alkylidene, C2-C6Alkenylene, C2-C6Alkynylene and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylene
Base, C2-C6Alkenylene and C2-C6Alkynylene, either individually or as a part of group, optionally by one or more independent
Ground substituent group selected from the group below replaces, which is made up of: C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen and C1-C6Alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base optionally by
One or more substituent groups independently selected from the group below replace, which is made up of: OR9And Cl；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl and condensed with phenyl group
4-6 unit monocycle heterocycle；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl and the 4-6 member list condensed with phenyl group
The substituent group that ring heterocycle is optionally independently selected by one or more from the following group replaces, which is made up of: R12、OR12、
NR13R14, OH, F, Cl and Br；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl,
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15, OH and F；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12
The substituent group that circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of: R18、OR18、C
(O)R18、C(O)OR18、SO2R18, OH, oxo, CN, F and Cl；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl, 5-11
Unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6Alkyl is optionally by one or more only
On the spot substituent group selected from the group below replaces, which is made up of: R21、OR21、C(O)OR21、NR22R23, OH, CN and F；Its
In each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one or more
A substituent group independently selected from the group below replaces, which is made up of: R24、OR24, CN, F and Cl；
R10And R11It is each independently selected from the following group at each occurrence, which is made up of: hydrogen and 5-6 unit's heteroaryl；
Wherein each R10And R115-6 unit's heteroaryl is optionally by one or more C1-C6Alkoxy replaces；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R12C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6It is halogenated
Alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, 6-10 member
Aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-10 member virtue
Base, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C6-C10
First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base and 4-12 circle heterocyclic ring base；Wherein each R18C1-C6Alkyl and C6-C10Member
The substituent group that aryl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-
C6Alkoxy, 5-6 unit's heteroaryl, CN, F and Cl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, 6-10 member aryl and
C3-C11Naphthenic base；Wherein each R21C1-C6Alkyl, 6-10 member aryl and C3-C11Naphthenic base is optionally replaced by CN；
R22And R23It is C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl,
C1-C6Alkoxy -C1-C6Alkyl and C3-C11Naphthenic base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
Exemplary compounds with formula (III) include but is not limited to:
Example 4；7；8；9；10；11；12；13；14；15；16；17；18；19；20；21；23；24；25；26；27；28；29；
30；31；32；33；34；35；36；37；38；39；42；43；44；45；46；47；48；49；50；51；52；53；54；55；56；
57；59；60；61；62；63；64；65；66；67；68；69；70；71；72；73；74；75；76；77；78；79；80；81；82；
83；84；85；86；87；88；89；90；91；92；93；94；95；96；97；98；99；100；101；102；103；104；105；
106；107；108；109；110；111；112；113；114；115；116；117；118；119；I-20；I-34；I-39；I-42；
I-43；I-44；I-46；I-47；I-48；I-49；I-50；I-51；I-52；I-53；I-54；I-55；I-56；I-57；I-58；I-
59；I-60；I-64；I-65；I-66；I-67；I-68；I-69；I-70；I-71；I-72；I-73；I-74；I-75；I-76；I-
77；I-78；I-79；I-80；I-81；I-82；I-83；I-84；I-85；I-86；I-88；I-89；I-90；I-91；I-92；I-
93；I-94；I-95；I-96；I-97；I-98；I-99；I-100；I-101；I-102；I-103；I-104；I-105；I-106；I-
107；I-108；I-109；I-110；I-111；I-112；I-113；I-114；I-119；I-120；I-121；I-123；I-124；
I-125；I-126；I-127；I-128；I-129；I-130；I-131；I-132；I-133；I-134；I-135；I-136；I-
137；I-138；I-139；I-140；I-141；I-142；I-143；I-144；I-145；I-146；I-147；I-148；I-149；
I-150；I-151；I-152；I-153；I-154；I-155；I-156；I-157；I-158；I-159；I-160；I-161；I-
162；I-163；I-164；I-165；I-166；I-167；I-168；I-169；I-170；I-171；I-172；I-175；I-176；
I-177；I-178；I-179；I-180；I-181；I-182；I-183；I-184；I-185；I-186；I-187；I-188；I-
189；I-190；I-191；I-192；I-193；I-194；I-195；I-196；I-197；I-198；I-199；I-200；I-201；
I-202；I-204；I-205；I-206；I-207；I-208；I-209；I-210；I-212；I-213；I-214；I-215；I-
216；I-217；I-218；I-219；I-221；I-222；I-223；I-224；I-225；I-226；I-227；I-228；I-229；
I-230；I-231；I-232；I-233；I-234；I-235；I-236；I-237；I-238；I-239；I-240；I-241；I-
242；I-243；I-244；I-245；I-246；I-247；I-248；I-249；I-250；I-251；I-252；I-253；I-254；
I-255；I-256；I-257；I-258；I-259；I-260；I-261；I-262；I-263；I-264；I-265；I-266；I-
267；I-268；I-269；I-270；I-271；I-272；I-273；I-274；I-275；I-276；I-277；I-278；I-279；
I-280；I-281；I-282；I-283；I-284；I-285；I-286；I-287；I-288；I-289；I-290；I-291；I-
292；I-293；I-294；I-295；I-296；I-297；I-298；I-299；I-300；I-301；I-302；I-303；I-304；
I-305；I-306；I-307；I-308；I-309；I-310；II-54；II-62；II-63；II-65；II-81；II-83；II-
84；II-87；II-91；II-92；II-93；II-94；II-95；II-96；II-97；II-98；II-99；II-100；II-101；
II-102；II-103；II-104；II-105；II-106；II-107；II-108；II-109；II-110；II-111；II-112；
II-113；II-114；II-115；II-116；II-117；II-118；II-119；II-120；II-121；II-122；II-123；
II-124；II-125；II-126；II-127；II-128；II-129；II-130；II-131；II-132；II-133；II-134；
II-135；II-136；II-137；II-138；II-139；II-140；II-141；II-144；II-145；II-146；II-147；
II-148；II-149；II-152；II-153；II-154；II-155；II-156；II-157；II-158；II-159；II-160；
II-161；II-162；II-163；II-164；II-165；II-166；II-167；II-168；II-169；II-170；II-171；
II-172；II-173；II-174；II-175；II-176；II-177；II-178；II-179；II-180；II-181；II-182；
II-183；II-184；II-185；II-186；II-187；II-188；II-189；II-190；II-191；II-192；II-193；
II-194；II-195；II-196；II-197；II-198；II-199；II-200；II-201；II-202；II-203；II-204；
II-205；II-206；II-207；II-208；II-209；II-210；II-211；II-212；II-213；II-214；II-215；
II-216；II-217；II-218；II-219；II-220；II-221；II-222；II-223；II-224；II-225；II-226；
II-227；II-228；II-229；II-230；II-231；II-232；II-233；II-234；II-235；II-236；II-237；
II-238；II-239；II-240；II-241；II-242；II-243；II-244；II-245；II-246；II-249；II-250；
II-259；II-260；II-261；II-262；II-263；II-264；II-265；II-266；II-267；II-268；II-269；
II-270；II-271；II-272；II-273；II-274；II-275；II-276；II-277；II-278；II-279；II-280；
II-281；II-282；II-283；II-284；II-285；II-286；II-287；II-288；II-289；II-290；II-291；
II-292；II-293；II-296；II-297；II-298；II-299；II-300；II-301；II-302；II-303；II-304；
II-305；II-306；II-307；II-308；II-309；II-310；II-311；II-312；II-313；II-314；II-315；
II-316；II-317；II-318；II-319；II-320；II-321；II-322；II-323；II-324；II-325；II-326；
II-327；II-328；II-329；II-330；II-331；II-332；II-333；II-334；II-335；II-336；II-337；
II-339；II-340；II-341；II-342；II-343；II-344；II-345；II-346；II-347；II-348；II-349；
II-350；II-351；II-352；II-353；II-354；II-355；II-356；II-357；II-358；II-359；II-360；
II-361；II-362；II-363；II-364；II-365；II-366；II-367；II-368；II-369；II-370；II-371；
II-372；II-373；II-374；II-375；II-376；II-377；II-378；II-379；II-380；II-381；II-382；
II-383；II-384；II-385；II-386；II-387；II-388；II-389；II-390；II-391；II-392；II-394；
II-396；II-397；II-398；II-399；II-400；II-401；II-402；II-403；II-404；II-405；II-406；
II-407；II-408；II-409；II-410；II-411；II-414；II-415；II-416；II-417；II-418；II-420；
II-421；II-422；II-423；II-424；II-425；II-426；II-427；II-428；II-429；II-430；II-431；
II-432；II-433；II-434；II-435；II-438；II-439；II-440；II-441；II-442；II-443；II-444；
II-445；II-446；II-447；II-448；II-449；II-450；II-451；II-452；II-453；II-454；II-455；
II-456；II-457；II-458；II-459；II-460；II-461；II-462；II-463；II-464；II-465；II-466；
II-467；II-468；II-469；II-470；II-471；II-472；II-473；II-474；II-475；II-476；II-477；
II-478；II-479；II-480；II-481；II-482；II-483；II-484；II-485；II-486；II-487；II-488；
II-489；II-490；II-491；II-492；II-493；II-494；II-495；II-496；II-497；II-498；II-499；
II-500；II-502；II-503；II-504；II-505；II-506；II-507；II-508；II-509；II-510；II-511；
II-512；II-513；II-514；II-515；II-516；II-517；II-518；II-519；II-520；II-521；II-522；
II-523；II-524；II-525；II-526；II-527；II-528；II-529；II-530；II-531；II-532；II-533；
II-534；II-535；II-536；II-537；II-538；II-539；II-540；II-541；II-542；II-543；II-544；
II-545；II-546；II-547；II-548；II-549；II-550；II-551；II-552；II-553；II-557；II-558；
II-559；II-560；II-561；II-562；II-563；II-564；II-565；II-566；II-567；II-568；II-569；
II-570；II-571；II-572；II-573；II-574；II-575；II-576；II-577；II-578；II-579；II-580；
II-581；II-582；II-583；II-584；II-585；II-586；II-587；II-588；II-589；II-590；II-591；
II-592；II-593；II-594；II-595；II-596；II-597；II-598；II-599；II-600；III-78；III-
100；III-103；III-118；III-119；III-120；III-121；III-122；III-123；III-124；III-125；
III-126；III-127；III-128；III-129；III-130；III-131；III-132；III-133；III-134；III-
135；III-136；III-137；III-138；III-139；III-140；III-141；III-142；III-144；III-145；
III-146；III-147；III-148；III-149；III-150；III-151；III-152；III-153；III-154；III-
155；III-156；III-157；III-158；III-159；III-160；III-161；III-162；III-163；III-164；
III-166；III-167；III-168；III-169；III-170；III-171；III-172；III-173；III-174；III-
175；III-176；III-177；III-178；III-179；III-180；III-181；III-182；III-183；III-184；
III-185；III-186；III-187；III-188；III-189；III-190；III-191；III-192；III-193；III-
194；III-195；III-196；III-197；III-198；III-200；III-201；III-202；III-203；III-204；
III-205；III-206；III-207；III-208；III-209；III-210；III-211；III-212；III-213；III-
214；III-215；III-216；III-217；III-218；III-219；III-220；III-221；III-222；III-223；
III-224；III-225；III-226；III-227；III-229；III-230；III-231；III-232；III-233；III-
234；III-235；III-237；And its pharmaceutically acceptable salt.
Algorithm (advanced chemistry Development Co., Ltd (Advanced Chemical is named by using title 2015Pack 2
Development)) or Struct=name nominating algorithm (asULTRA is v.12.0.2.1076 or professional
A part of version 15.0.0.106) name the compound of the present invention.
The compounds of this invention can exist with stereoisomer form, wherein there is asymmetric or chiral centre.According to chirality
The configuration of substituent group around carbon atom, these stereoisomers are " R " or " S ".Term " R " used herein and " S " are
1974 Recommendations for Section E, Fundamental Stereochemistry [IUPAC of IUPAC
Part E basic stereoscopic chemistry suggestion in 1974], in: Pure Appl.Chem. [purely and applied chemistry] 1976,45:13-
Configuration defined in 30.The present invention covers various stereoisomers and its mixture, and these be specifically included in it is of the invention
In range.Stereoisomer includes the mixed of enantiomter and diastereoisomer and enantiomer or diastereomer
Close object.The individual stereoisomer of the compound of the present invention can be from the commercially available starting comprising asymmetric or chiral centre
Material is synthetically prepared, or by preparing racemic mixture, then passes through fractionation well known within the skill of those ordinarily skilled
Method is through being synthetically prepared.These method for splitting examples are as follows: (1) mixture of enantiomter and chiral auxiliary are attached, are passed through
The mixture for the diastereoisomer that precipitating or chromatographic isolation obtain, and optically pure product is optionally discharged from auxiliary agent,
Described in following: Furniss, Hannaford, Smith and Tatchell, " Vogel ' s Textbook of Practical
Organic Chemistry [the practical organic chemistry textbook of Wo Geer] ", the 5th edition (1989), Longman
Scientific&Technical [scientific & technical corporation, Longman], Essex (Essex) CM202JE, England, or (2) in chirality
The mixture or (3) fractional recrystallisation method of optical enantiomorphs are directly separated in chromatographic column.
The compound of the present invention can exist with cis or trans isomers, and the substituent group in middle ring can be by relative to that
This ring same side (cis-) or be relative to each other attached in such mode of the opposite side of ring (trans-).For example, cyclobutane
Can exist with cis or trans configuration, and can exist with the mixture of individual isomer or cis and trans isomer.This hair
The individual cis or trans isomers of bright compound can be used selective organic transformation and pass through from commercially available starting material
It is synthetically prepared, or the mixture by purifying cis and trans isomer is prepared in the form of individual isomer.Such methods are these
Field is well-known to the ordinarily skilled artisan, and may include by precipitating or chromatographic isolation isomers.
It should be appreciated that the compound of the present invention can have tautomeric form and geometric isomer, and these shapes
Formula also constitutes an aspect of of the present present invention.
Present disclosure include with formula (I) all pharmaceutically acceptable isotope labellings compound, one of them or
Multiple atoms are by with same atoms ordinal number but atomic mass or mass number are different from the prevailing atom matter of nature
The atom of amount or mass number replaces.It is suitble to include the example of isotope in the compound of present disclosure to include same position below
Element: hydrogen is for example2H and3H, carbon is for example11C、13C and14C, chlorine is for example36Cl, fluorine is for example18F, iodine is for example123I and125I, nitrogen is for example13N
With15N, oxygen is for example15O、17O and18O, phosphorus is for example32P and sulphur are for example35S.The compound of certain isotope labellings with formula (I),
Such as mix it is radioisotopic those, can be used for drug and/or substrate tissue distribution research.Radioactive isotope tritium is (i.e.3H) and carbon-14 (i.e.14C) this purpose is used especially for because being easily incorporate into and being easy detection.(i.e. with heavier isotope such as deuterium2H certain treatment advantages as caused by bigger metabolic stability can be provided by) replacing, such as increased Half-life in vivo and be subtracted
Few volume requirements, and therefore in some cases may be preferred.(such as with Positron emitting isotopes11C、18F、15O
With13N) carrying out replacing can use in positron emission computerized tomography (PET) research, to check substrate receptor occupancy.Have
The compound of the isotope labelling of formula (I) usually can be by routine techniques well known by persons skilled in the art, or passes through similar
The method of method those of described in the appended example replaces what is previously used not mark using the reagent of isotope labelling appropriate
Reagent is remembered to prepare.
Therefore, the formula figure in this specification can only indicate possible tautomeric form, geometrical isomerism form or three-dimensional different
One of configuration formula.It should be understood that the present invention cover any tautomeric form, geometrical isomerism form or stereoisomeric forms in any ratio and
Its mixture, and it is different to be not limited only to any tautomeric form, geometrical isomerism form or the solid that utilize in Shi Tunei
Configuration formula.
Compound with formula (I) can be used by the form of pharmaceutically acceptable salt.Phrase is " pharmaceutically acceptable
Salt " means to be suitable for being in contact with the tissue of the mankind and lower animal within a reasonable range of medical judgment, without unsuitable
Toxicity, stimulation, allergic reaction etc., and those of match salt with reasonable benefit/risk ratio.
Pharmaceutically acceptable salt has been described in S.M.Berge et al. J.Pharmaceutical Sciences [drug
Scientific Magazine], in 1977,66:1-19.
Compound with formula (I) can containing alkalinity or acid functionality or both, and it is desirable that when, can be by making
Pharmaceutically acceptable salt is converted into suitable acid or alkali.It can be finally recovered and purify the compound of the present invention mistake
These salt are prepared in situ in journey.
The example of acid-addition salts includes but is not limited to acetate, adipate, alginate, citrate, aspartic acid
Salt, benzoate, benzene sulfonate, disulfate, butyrate, camphor hydrochlorate, camsilate, digluconate, phosphoglycerol
Salt, Hemisulphate, enanthate, caproate, fumarate, hydrochloride, hydrobromate, hydriodate, 2- isethionate are (different
Vulcanize hydroxy acid salt), lactate, malate, maleate, mesylate, nicotinate, 2- naphthalene sulfonate, oxalates, palmitinic acid
Salt, pectate, persulfate, 3- phenpropionate, picrate, pivalate, propionate, succinate, tartrate, sulphur
Cyanate, phosphate, glutamate, bicarbonate, tosilate and undecanoate.In addition, Basic nitrogen-containing groups
Can be quaternized with following reagent: elementary alkyl halide, such as, but not limited to, methyl, ethyl, propyl and butyl chloride,
Bromide and iodide；Dialkyl sulfate, such as dimethyl, diethyl, dibutyl and diamyl sulfate；Long chain halide,
The such as, but not limited to, chloride, bromide and iodide of decyl, lauryl, myristyl and stearyl；Arylalkyl halide
Such as benzyl and phenylethyl bromide.Thus to obtain water-soluble or oil-soluble or dispersible products.It can be used for being formed pharmaceutically
The example of the acid of acceptable acid-addition salts includes following inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid；It is shown under and
Machine acid, such as acetic acid, fumaric acid, maleic acid, 4- toluenesulfonic acid, succinic acid and citric acid.
Base addition salts can be prepared in situ during being finally recovered and purifying the compound of the present invention, by portion containing carboxylic acid
Divide anti-with suitable alkali (hydroxide, carbonate or the bicarbonate of such as, but not limited to, pharmaceutically acceptable metal cation)
It answers, or is reacted with ammonium hydroxide or organic primary, secondary or tertiary amine.Pharmaceutically acceptable salt includes but is not limited to be based on alkali metal or alkaline earth
The cation of metal, such as, but not limited to lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and aluminium salt etc. and nontoxic quaternary ammonium and amine sun
Ion, including ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethamine etc..Other can
The example for being used to form the organic amine of base addition salts includes ethylenediamine, ethanol amine, diethanol amine, piperidines, piperazine etc..
Term " pharmaceutically acceptable prodrug " or " prodrug " as used herein refer to this hair with cleavable moiety
The derivative of bright compound.These derivatives are by solvolysis or become have pharmaceutical activity in vivo in physiological conditions
The compound of the present invention.The prodrug of the compound of the present invention is suitable for and the mankind and low in reliable medical judgment scope
The tissue of animal contacts without excessive toxicity, irritation, allergic reaction etc., match with reasonable benefit/risk ratio and
It can be effectively used for its desired use.
The present invention consider formed by synthesizing mean or converted by the vivo biodistribution of prodrug to be formed with formula (I)
Compound.
Compound described herein can exist with non-solvated and solvation form, including hydrated form, Ru Banshui
Close object.In general, for purposes of the present invention, the solvation formed with pharmaceutically acceptable solvent (especially such as water and ethyl alcohol)
Form is equal to nonsolvated forms.
Pharmaceutical composition
When being used as drug, the compound of the present invention is usually given in the form of pharmaceutical composition.Such composition can
By by preparing in a manner of known to pharmaceutical field, and include therapeutically effective amount compound with formula (I) or its pharmaceutically may be used
The salt and pharmaceutically acceptable carrier of receiving.Phrase " pharmaceutical composition ", which refers to, to be suitable for administration to use for medicine or veterinary science
The composition on way.
Term " pharmaceutically acceptable carrier " as used herein means any kind of nontoxic, inert solid, half admittedly
Body or liquid filler, diluent, encapsulating material or formulation aid.
Application method
Can be used any amount and it is any give approach and give compound and composition to subject be used to treat or prevent
Cystic fibrosis, pancreatic insufficiency, Sjogren syndrome (SS), chronic obstructive pulmonary disease (COLD) or Chronic obstructive airways disease
Sick (COAD).
Term " giving " is the method for instigating compound to contact with subject.It therefore, can be by injection (i.e. intravenously,
In intramuscular, intradermal, subcutaneous, duodenum, in parenteral or peritonaeum) give compound.Furthermore, it is possible to by sucking (such as through
Nose) give compound described herein.In addition, these compounds can transdermally, locally and via implantation be given.At certain
It, can oral delivery compound and combinations thereof in a little embodiments.Can with per rectum, buccal, intravaginal, through eye or by being blown into
Deliver the compound.Depending on the property of obstruction and illness, can be used compound and combinations thereof prophylactically, acutely and
The obstacle and illness that chronically treatment CFTR- is adjusted.In general, the host or subject in each in these methods are
People, although as described above, other mammals can also be benefited from giving in compound and combinations thereof.
The compound of the present invention can be used as the regulator of CFTR.Therefore, these compounds and composition are particularly useful for controlling
It treats and is directed to the hyperfunction or inactive disease of CFTR activity, obstruction and illness or mitigates its seriousness or progress.Therefore, this hair
It is bright provide it is a kind of for treating the cystic fibrosis in subject, pancreatic insufficiency, Sjogren syndrome (SS), chronic obstructive
The method of tuberculosis (COLD) or chronic obstructive airway disease (COAD), wherein this method includes giving to control to the subject
A effective amount of compound as described above with formula (I) or its pharmaceutically acceptable salt or its preferred embodiment are treated, wherein
It is with or without pharmaceutically acceptable carrier.Particularly, this method is for treating or preventing cystic fibrosis.It is more specific at one
Embodiment in, cystic fibrosis be as I, II, III, IV, V and/or VI type mutation caused by.
In a specific embodiment, the present invention is provided to the compounds of this invention used in medicine or its pharmacy
Upper acceptable salt or the pharmaceutical composition including the compounds of this invention.In a specific embodiment, the present invention provides use
In in treatment cystic fibrosis, pancreatic functions are complete, Sjogren syndrome (SS), chronic obstructive pulmonary disease (COLD) or chronic obstruction
The compounds of this invention or its pharmaceutically acceptable salt used in property airway disorders (COAD) include the compounds of this invention
Pharmaceutical composition.In a more specific embodiment, the present invention is provided to this hairs used in treatment cystic fibrosis
Bright compound or pharmaceutical composition comprising the compounds of this invention.In a more specific embodiment, cystic fibrosis be by
I, caused by the mutation of II, III, IV, V and/or VI type.
One embodiment is related to the use according to the compound or its pharmaceutically acceptable salt of formula (I) in medicine preparation
On the way.The drug optionally may include one or more other therapeutic agents.In some embodiments, which is used in capsule fibre
Dimensionization, pancreatic insufficiency, Sjogren syndrome (SS), chronic obstructive pulmonary disease (COLD) or chronic obstructive airway disease (COAD)
Treatment in use.In a specific embodiment, the drug in the treatment of cystic fibrosis for using.More at one
In specific embodiment, cystic fibrosis is as caused by the mutation of I, II, III, IV, V and/or VI type.
The invention further relates to the compound or its pharmaceutically acceptable salt according to formula (I) in manufacture for treating capsule fibre
Dimensionization, Sjogren syndrome, pancreatic insufficiency, chronic obstructive pulmonary disease and chronic obstructive airway disease drug in purposes.
The drug optionally may include one or more other therapeutic agents.In a specific embodiment, the present invention relates to bases
The compound or its pharmaceutically acceptable salt of formula (I) are manufacturing the purposes in the drug for treating cystic fibrosis.One
In a more specific embodiment, cystic fibrosis is as caused by the mutation of I, II, III, IV, V and/or VI type.
In one embodiment, the present invention provide comprising the compounds of this invention or its pharmaceutically acceptable salt and one kind or
The pharmaceutical composition of a variety of other therapeutic agents.In another embodiment, the present invention provide comprising the compounds of this invention or its
The pharmaceutical composition of pharmaceutically acceptable salt and one or more other therapeutic agents, wherein other therapeutic agent is selected from down
Group, the group are made up of: CFTR regulator and CFTR reinforcing agent.In another embodiment, it includes this hair that the present invention, which provides,
The pharmaceutical composition of bright compound or its pharmaceutically acceptable salt and one or more other therapeutic agents, wherein other controls
Treating agent is CFTR regulator.
In one embodiment, the present invention provide comprising the compounds of this invention or its pharmaceutically acceptable salt and one kind or
The pharmaceutical composition of a variety of other therapeutic agents.In one embodiment, it includes the compounds of this invention or its medicine that the present invention, which provides,
The pharmaceutical composition of acceptable salt, a kind of synergist and one or more other corrigents on.In one embodiment
In, the present invention provides the pharmaceutical composition comprising the compounds of this invention and another therapeutic agent.In a specific embodiment, should
Another therapeutic agent is cystic fibrosis therapies agent.In one embodiment, the present invention provides the cystic fibrosis for the treatment of subject
Method comprising give the compounds of this invention or its pharmaceutically acceptable salt and one or more other therapeutic agents.?
In another embodiment, the present invention provides the method for the cystic fibrosis for the treatment of subject comprising gives the compounds of this invention
Or its pharmaceutically acceptable salt and one or more other therapeutic agents, wherein other therapeutic agent is selected from the group, the group by
Consisting of: CFTR regulator and CFTR reinforcing agent.In one embodiment, the present invention provides the capsule fiber for the treatment of subject
The method of change comprising the compounds of this invention or its pharmaceutically acceptable salt and one or more other therapeutic agents are given,
Wherein other therapeutic agent is CFTR regulator.In one embodiment, the present invention provides the cystic fibrosis for the treatment of subject
Method comprising give the compounds of this invention or its pharmaceutically acceptable salt and another therapeutic agent.It is specific real at one
It applies in example, which is cystic fibrosis therapies agent.In one embodiment, the present invention provides the capsule for the treatment of subject
The method of property fibrosis comprising give the compounds of this invention or its pharmaceutically acceptable salt of therapeutically effective amount.At one
In specific embodiment, which is a kind of synergist and one or more other corrections
Agent.In another embodiment, which is selected from the group, which is made up of: CFTR is adjusted
Agent and CFTR reinforcing agent.In another embodiment, which is CFTR regulator.More at one
In the embodiment of body, cystic fibrosis is as caused by the mutation of I, II, III, IV, V and/or VI type.
The compound of the present invention or its pharmaceutically acceptable salt can be used as unique activating agent and give, or can be with other
Therapeutic agent (including other compounds or its pharmaceutically acceptable salt) is given altogether, and the other therapeutic agents show identical or phase
As therapeutic activity and determine that give be safely effectively for this combination.The compound of the present invention can give altogether to
Subject.Term " giving altogether " refers to two or more different therapeutic agents in single drug composition or separated medicine
Subject is given in compositions.Therefore, it gives altogether and is related to giving the single medicine comprising two or more therapeutic reagents simultaneously
Compositions give two or more different components to same subject in the identical or different time.
The compound of the present invention or its pharmaceutically acceptable salt can be one or more other with therapeutically effective amount
Therapeutic agent gives the disease for being treated CFTR mediation altogether, and wherein the example of therapeutic agent includes but is not limited to antibiotic (such as amino
Glycoside, colistin, aztreonam, Ciprofloxacin and azithromycin), expectorant (such as hypertonic saline, acetylcysteine, Ah
Method dornase and Niu Fusuo), pancreatin replenishers (such as pancreatin and pancreatic lipase), Epithelial sodium channel blocking agent (ENaC) suppression
Preparation, CFTR regulator (such as CFTR synergist, CFTR corrigent) and CFTR reinforcing agent.In one embodiment, CFTR
The disease of mediation is cystic fibrosis, chronic obstructive pulmonary disease (COPD), scheroma, pancreatic insufficiency or Sjogren syndrome.?
In one embodiment, the disease that CFTR is mediated is cystic fibrosis.In one embodiment, the compound of the present invention or its pharmacy
Upper acceptable salt can be given altogether with one or two kinds of CFTR regulators and a kind of CFTR reinforcing agent.In one embodiment,
The compound of the present invention or its pharmaceutically acceptable salt can be with a kind of synergist, one or more corrigents and one kind
CFTR reinforcing agent is given altogether.In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt can be with one kind
Or a variety of CFTR regulators are given altogether.In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt can be with
It is given altogether with a kind of CFTR regulator.In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt can be with
It is given altogether with two kinds of CFTR regulators.In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt can be with
It is given altogether with three kinds of CFTR regulators.In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt can be with
It is given altogether with a kind of synergist and one or more corrigents.In one embodiment, the compound of the present invention or its pharmaceutically
Acceptable salt can be given altogether with a kind of synergist and two kinds of corrigents.In one embodiment, the compound of the present invention or
Its pharmaceutically acceptable salt can be given altogether with a kind of synergist.In one embodiment, the compound of the present invention or its medicine
Acceptable salt can be given altogether with one or more corrigents on.In one embodiment, the compound of the present invention or its
Pharmaceutically acceptable salt can be given altogether with a kind of corrigent.In one embodiment, the compound of the present invention or its pharmacy
Upper acceptable salt can be given altogether with two kinds of corrigents.
The example of CFTR synergist include but is not limited to she cut down Kato (VX-770), CTP-656, NVS-QBW251,
FD1860293, GLPG2451, GLPG1837, PTI-808, N- (3- carbamoyl -5,5,7,7- tetramethyl -5,7- dihydros -
4H- thieno [2,3-c] pyrans -2- base)-IH- pyrazoles -5- formamide and 3- amino-N- [(2S) -2- hydroxypropyl] -5-
{ [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine-2-carboxamide.The example of synergist is also disclosed in following publication: WO
2005120497、WO 2008147952、WO 2009076593、WO 2010048573、WO 2006002421、WO
2008147952, WO 2011072241, WO 2011113894, WO 2013038373, WO 2013038378, WO
2013038381、WO 2013038386、WO 2013038390、WO 2014180562、WO 2015018823、WO2014/
180562, WO 2015018823, WO 2016193812 and U. S. application 15/502,892.
In one embodiment, synergist can be selected from the group, which is made up of:
She cuts down Kato (VX-770, N- (2,4- di-t-butyl -5- hydroxy phenyl) -4- oxo-Isosorbide-5-Nitrae-dihydroquinoline -3- first
Amide)；
GLPG1837；
GLP-2451；
PTI-808；
CTP-656；
NVS-QBW251；
FD1860293；
2- (2- fluorobenzoyl amido) -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -3- first
Amide；
N- (3- carbamyl -5,5,7,7- tetramethyl -4,7- dihydro -5H- thieno [2,3-c] pyrans -2- bases) -1H-
Pyrazoles -5- formamide；
2- (2-Hydroxylbenzamide base) -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -3-
Formamide
- 5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrrole of 2- (1- hydroxyl cyclopropanecarbonyl amido)
It mutters -3- formamide；
5,5,7,7- tetramethyl -2- (2- (trifluoromethyl) benzamido) -5,7- dihydro -4H- thieno [2,3-c] pyrrole
It mutters -3- formamide；
2- (2- hydroxy-2-methyl propionamido-) -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrrole
It mutters -3- formamide；
- 5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3- of 2- (1- (hydroxymethyl) cyclopropanecarbonyl amido)
C] pyrans -3- formamide；
- 5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3- of 2- (3- hydroxyl -2,2- dimethylpropionamide base)
C] pyrans -3- formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -5- first
Base -1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -5- ring
Propyl -1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -5- is different
Propyl -1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -5-
(trifluoromethyl) -1H- pyrazole-3-formamide；
5- tert-butyl-n-(3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -
2- yl) -1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -5- second
Base -1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -3- second
Base -4- methyl-1 H- pyrazoles -5- formamide；
2- (2- hydroxypropanamide base) -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -3- first
Amide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -4-
Chloro- 1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases)-Isosorbide-5-Nitrae,
6,7- oxinanes simultaneously [4,3-c] pyrazole-3-formamide；
The bromo- N- of 4- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2-
Base) -1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -4-
Chloro- 5- methyl-1 H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3-c] pyrans -2- bases) -4- first
Base -1H- pyrazole-3-formamide；
- 5,5,7,7- tetramethyl -5,7- dihydro -4H- thieno [2,3- of 2- (2- hydroxyl -3,3- amide dimethyl butyrate base)
C] pyrans -3- formamide；
2- [(2- hydroxy-4-methyl-valeryl) amino] -5,5,7,7- tetramethyl -4H- thieno [2,3-c] pyrans -3-
Formamide；
5- (2- Mehtoxy-ethoxy) -1H- pyrazoles -3- formic acid (3- carbamyl -5,5,7,7- tetramethyls -4,7- bis-
Hydrogen -5H- thieno [2,3-c] pyrans -2- base)-amide；
N- (3- carbamyl -5,5,7,7- tetramethyl -4H- thieno [2,3-c] pyrans -2- bases) -4- (3- methoxy propyl
Base) -1H- pyrazole-3-formamide；
N- (3- carbamyl -5,5,7,7- tetramethyl -4H- thieno [2,3-c] pyrans -2- bases) -4- (2- ethyoxyl second
Base) -1H- pyrazole-3-formamide；
2- [[(2S) -2- hydroxyl -3,3- Dimethyl-butyryl] amino] -5,5,7,7- tetramethyl -4H- thienos [2,3-
C] pyrans -3- formamide；
2- [[(2R) -2- hydroxyl -3,3- Dimethyl-butyryl] amino] -5,5,7,7- tetramethyl -4H- thienos [2,3-
C] pyrans -3- formamide；
2- [(2- hydroxyl -2,3,3- trimethyl-bytyry) amino] -5,5,7,7- tetramethyl -4H- thienos [2,3-c]
Pyrans -3- formamide；
[5- [(3- carbamyl -5,5,7,7- tetramethyl -4H- thieno [2,3-c] pyrans -2- bases) carbamyl] pyrrole
Azoles -1- base] methyl dihydrogen phosphoric acid ester；
[3- [(3- carbamyl -5,5,7,7- tetramethyl -4H- thieno [2,3-c] pyrans -2- bases) carbamyl] pyrrole
Azoles -1- base] methyl dihydrogen phosphoric acid ester；
N- (3- carbamyl -5,5,7,7- tetramethyl -4H- thieno [2,3-c] pyrans -2- bases) -4- (dislike by Isosorbide-5-Nitrae-two
Alkane -2- base) -1H- pyrazole-3-formamide；
5,5,7,7- tetramethyl -2- [[(2S) -3,3,3- tri- fluoro- 2- hydroxy-2-methyl-propionos] amino] -4H- thiophene
And [2,3-c] pyrans -3- formamide；
2- [[(2S) -2- hydroxypropanoyl] amino] -5,5,7,7- tetramethyl -4H- thieno [2,3-c] pyrans -3- first
Amide；
3- amino-N- (2- hydroxy-2-methyl propyl) -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- first
Amide；
3- amino-N- [(4- hydroxyl -1- methyl piperidine -4- base) methyl] -5- { [4- (trifluoromethoxy) phenyl] sulphonyl
Base } pyridine-2-carboxamide；
3- amino-N- (3- hydroxyl -2,2- dimethyl propyl) -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -
2- formamide；
3- amino -5- [(4- fluorophenyl) sulfonyl]-N- [(1- hydroxycyclopropyl) methyl] pyridine-2-carboxamide；
3- amino -5- [(4- fluorophenyl) sulfonyl]-N- [(2R) -3,3,3- tri- fluoro- 2- hydroxypropyls] pyridine -2- formyl
Amine；
3- amino -5- [(3- fluorophenyl) sulfonyl]-N- (2- hydroxy-2-methyl propyl) pyridine-2-carboxamide；
3- amino-N- [2- (cyclopropylamino) -2- oxoethyl] -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyrrole
Pyridine -2- formamide；
(3- amino -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- base) (azetidine -1- base) first
Ketone；
(3- amino -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- base) [3- (hydroxymethyl) azetidin
Alkane -1- base] ketone；
(3- amino -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- base) (3- fluorine azetidine -1- base)
Ketone；
3- amino-N- [(2R) -2- hydroxy-3-methoxy propyl] -5- { [4- (trifluoromethyl) phenyl] sulfonyl } pyridine -
2- formamide；
(3- amino -5- { [2- fluoro- 4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- base) (3- hydroxyazetidinium
Alkane -1- base) ketone；
(3- amino -5- { [2- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- base) (3,3- difluoro azetidines -
1- yl) ketone；
Racemic -3- amino-N- [(3R, 4S) -4- hydroxy tetrahydro -2H- pyrans -3- base] -5- { [2- (trifluoromethoxy)
Phenyl] sulfonyl } pyridine-2-carboxamide；
3- amino -5- [(4,4- difluoropiperdin -1- base) sulfonyl]-N- (3,3,3- tri- fluoro- 2- hydroxypropyl) pyridine -2-
Formamide；
(3- amino -5- { [2- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- base) [3- hydroxyl -3- (trifluoromethyl)
Azetidine -1- base] ketone；
3- amino-N- (2- hydroxy-4-methyl amyl) -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- first
Amide；
(3- amino -5- { [4- (trifluoromethyl) phenyl] sulfonyl } pyridine -2- base) (3- hydroxy-3-methyl azetidin
Alkane -1- base) ketone；
3- amino-N- (3,3,3- tri- fluoro- 2- hydroxypropyl) -5- { [4- (trifluoromethyl) piperidin-1-yl] sulfonyl } pyrrole
Pyridine -2- formamide；
3- amino-N- [2- hydroxyl -1- (4- methoxyphenyl) ethyl] -5- { [4- (trifluoromethoxy) phenyl] sulfonyl }
Pyridine-2-carboxamide；
3- amino -5- [(3,3- difluoro azetidine -1- base) sulfonyl]-N- (3,3,3- tri- fluoro- 2- hydroxypropyl)
Pyridine-2-carboxamide；
3- amino -5- { [2- fluoro- 4- (trifluoromethyl) phenyl] sulfonyl }-N- [(2S) -2- hydroxypropyl] pyridine -2- first
Amide；
3- amino -5- { [2- fluoro- 4- (trifluoromethyl) phenyl] sulfonyl }-N- [(2R) -2- hydroxy-3-methoxy propyl]
Pyridine-2-carboxamide；
3- amino-N- [2- oxo -2- (propane -2- base amino) ethyl] -5- { [4- (trifluoromethyl) phenyl] sulfonyl }
Pyridine-2-carboxamide；
(3- amino -5- { [4- (trifluoromethyl) phenyl] sulfonyl } pyridine -2- base) [3- hydroxyl -3- (trifluoromethyl) nitrogen
Azetidine -1- base] ketone；
3- amino -5- { [2- fluoro- 4- (trifluoromethyl) phenyl] sulfonyl }-N- [(3R)-tetrahydrofuran -3- ylmethyl] pyrrole
Pyridine -2- formamide；
(3- amino -5- { [2- fluoro- 4- (trifluoromethyl) phenyl] sulfonyl } pyridine -2- base) [3- hydroxyl -3- (fluoroform
Base) azetidine -1- base] ketone；
3- amino -5- { [2- fluoro- 4- (trifluoromethyl) phenyl] sulfonyl }-N- [(3S)-tetrahydrofuran -3- ylmethyl] pyrrole
Pyridine -2- formamide；
3- amino -5- { [2- fluoro- 4- (trifluoromethoxy) phenyl] sulfonyl }-N- [(3S)-tetrahydrofuran -3- ylmethyl]
Pyridine-2-carboxamide；
3- amino-N- [2- hydroxyl -3- (2,2,2- trifluoro ethoxy) propyl] -5- { [4- (trifluoromethyl) phenyl] sulphonyl
Base } pyridine-2-carboxamide；
3- amino-N- (3- tert-butoxy -2- hydroxypropyl) -5- { [2- fluoro- 4- (trifluoromethyl) phenyl] sulfonyl } pyrrole
Pyridine -2- formamide；
[3- amino -5- (phenyl sulfonyl) pyridine -2- base] [3- hydroxyl -3- (trifluoromethyl) azetidine -1- base]
Ketone；
{ 3- amino -5- [(3- fluorophenyl) sulfonyl] pyridine -2- base } [3- hydroxyl -3- (trifluoromethyl) azetidine -
1- yl] ketone；And
3- amino-N- [(2S) -2- hydroxypropyl] -5- { [4- (trifluoromethoxy) phenyl] sulfonyl } pyridine -2- formyl
Amine.
The non-limiting example of corrigent includes Lu Makatuo (VX-809), 1- (dioxa between 2,2- bis- fluoro- 1,3- benzos
Cyclopentene -5- base)-N- { 1- [(2R) -2,3- dihydroxypropyl] fluoro- 2- of -6- (1- hydroxy-2-methyl propane -2- base) -1H- Yin
Diindyl -5- base } cyclopropane carboxamide (VX-661), VX-983, GLPG2851, GLPG2222, GLPG2665, GLPG2737,
GLPG3221, PTI-801, VX-152, VX-440, VX-445, VX-659, FDL169, FDL304, FD2052160 and
FD2035659.The example of corrigent is also disclosed in U. S. application 14/925649,14/926727,15/205512,15/
287922, in 15/287911,15/287922,15/287911 and 15/492094.
In one embodiment, which can be selected from the group, which is made up of；
Lu Makatuo (VX-809)；
1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base)-N- { 1- [(2R) -2,3- dihydroxypropyl] -
The fluoro- 2- of 6- (1- hydroxy-2-methyl propane -2- base) -1H- indoles -5- base } cyclopropane carboxamide (VX-661)；
PTI-801；
VX-983；
GLPG2665；
GLPG2851；
GLPG2222；
GLPG2737；
GLPG3221；
VX-152；
VX-440；
VX-659；
VX-445；
FDL169
FDL304；
FD2052160；
FD2035659；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- methoxyl group -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -6- methyl -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- methyl -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -6- methoxyl group -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- (difluoro-methoxy) -3,4- dihydro -2H- chromene -2- base] naphthenic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- (difluoro-methoxy) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- methoxyl group -3,4- dihydro -2H- chromene -2- base] naphthenic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- fluoro -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- ({ 3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl
Base } amino) -7- methyl -3,4- dihydro -2H- chromene -2- base] benzoyl } amino) -1- methylcyclopentanecarboxylic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- methyl -3,4- dihydro -2H- chromene -2- base]-N- [(2R) -2,3- dihydroxypropyl] benzamide；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- (2- methoxy ethoxy) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -7- (benzyloxy) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) ring
Propyl] carbonyl } amino) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- (2- fluorine ethyoxyl) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- (trifluoromethyl) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- (trifluoromethyl) -3,4- dihydro -2H- chromene -2- base] naphthenic acid；
4- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- methoxyl group -3,4- dihydro -2H- chromene -2- base] benzoic acid；
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -8- fluoro -3,4- dihydro -2H- chromene -2- base] benzoic acid；
4- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
4- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) -7- (difluoro-methoxy) -3,4- dihydro -2H- chromene -2- base] benzoic acid；
Racemic -3- [(2R, 4S) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl
Base] carbonyl } amino) tetrahydro -2H- pyrans -2- base] benzoic acid；
Racemic -4- [(2R, 4S) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl
Base] carbonyl } amino) tetrahydro -2H- pyrans -2- base] benzoic acid；
3- [(2S, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) tetrahydro -2H- pyrans -2- base] benzoic acid；
3- [(2R, 4S) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) tetrahydro -2H- pyrans -2- base] benzoic acid；
Racemic -3- [(2R, 4S, 6S) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) ring
Propyl] carbonyl } amino) -6- phenyl tetrahydro -2H- pyrans -2- base] benzoic acid；
3- [(2S, 4R, 6R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl
Base } amino) -6- phenyl tetrahydro -2H- pyrans -2- base] benzoic acid；
3- [(2R, 4S, 6S) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl
Base } amino) -6- phenyl tetrahydro -2H- pyrans -2- base] benzoic acid；
4- [(2R, 4S) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl }
Amino) tetrahydro -2H- pyrans -2- base] benzoic acid；
3- cyclobutyl -4- [4- (morpholine -4- base) piperidin-1-yl] -1- phenyl -1H- pyrazolo [3,4-b] pyridine -6- first
Acid；
3- cyclobutyl -1- phenyl -4- { 4- [(pyrrolidin-1-yl) methyl] piperidin-1-yl } -1H- pyrazolo [3,4-b] pyrrole
Pyridine -6- formic acid；
5- [(2R, 4R) -4- { [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,3] benzene
And dioxole -7- carbonyl] amino -7- methoxyl group -3,4- dihydro -2H-1- chromene -2- base] pyrazine -2- first
Acid；
6- [(2R, 4R) -4- { [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,3] benzene
And dioxole -7- carbonyl] amino -7- (trifluoromethoxy) -3,4- dihydro -2H-1- chromene -2- base] pyrrole
Pyridine -3- formic acid；
Trans- -4- [(2S, 4S) -4- [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,
3] benzodioxole -7- carbonyl] amino } -7- (trifluoromethoxy) -3,4- dihydro -2H-1- chromene -2- base]
Hexamethylene -1- formic acid；
[{ [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- is simultaneously by (2R, 4R) -7- (difluoro-methoxy) -4- by 6-
[2,3-f] [1,3] benzodioxole -7- carbonyl] amino } -3,4- dihydro -2H-1- chromene -2- base] pyridine -
3- formic acid；
Trans- -4- [(2S, 4S) -4- [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,
3] benzodioxole -7- carbonyl] amino } -7- methoxyl group -3,4- dihydro -2H-1- chromene -2- base] hexamethylene
Alkane -1- formic acid；
Trans--the 4- of ethyl [(2S, 4S) -7- (difluoro-methoxy) -4- { [fluoro- 7- methyl -6,7- dihydro-of (7R) -2,2- bis-
2H- furans simultaneously [2,3-f] [1,3] benzodioxole -7- carbonyl] amino } -3,4- dihydro -2H-1- chromene -
2- yl] hexamethylene -1- formic acid esters；
Cis- -4- [(2R, 4R) -4- [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,
3] benzodioxole -7- carbonyl] amino } -7- (trifluoromethoxy) -3,4- dihydro -2H-1- chromene -2- base]
Hexamethylene -1- formic acid；
Trans- -4- [(2S, 4S) -7- (difluoro-methoxy) -4- { [fluoro- 7- methyl -6,7- dihydro -2H- of (7R) -2,2- bis-
Furans simultaneously [2,3-f] [1,3] benzodioxole -7- carbonyl] amino } -3,4- dihydro -2H-1- chromene -2-
Base] hexamethylene -1- formic acid；
1- [(2R, 4R) -4- { [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,3] benzene
And dioxole -7- carbonyl] amino -7- (trifluoromethoxy) -3,4- dihydro -2H-1- chromene -2- base] cyclopropyl
Alkane -1- formic acid；
Trans- -4- [(2R, 4R) -4- { [fluoro- 5- methyl -6,7- dihydro -2H, 5H- indeno [5,6-d] of (5S) -2,2- bis-
[1,3] dioxole -5- carbonyl] amino } -7- (trifluoromethoxy) -3,4- dihydro -2H-1- chromene -2- base]
Hexamethylene -1- formic acid；
Trans- -4- [(2R, 4R) -4- { [fluoro- 5- methyl -6,7- dihydro -2H, 5H- indeno [5,6-d] of (5S) -2,2- bis-
[1,3] dioxole -5- carbonyl] amino } -7- methoxyl group -3,4- dihydro -2H-1- chromene -2- base] hexamethylene -
1- formic acid；
Trans- -4- [(2R, 4R) -4- [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,
3] benzodioxole -7- carbonyl] amino } -7- methoxyl group -3,4- dihydro -2H-1- chromene -2- base] hexamethylene
Alkane -1- formic acid；
Trans- -4- [(2R, 4R) -7- (difluoro-methoxy) -4- { [fluoro- 7- methyl -6,7- dihydro -2H- of (7R) -2,2- bis-
Furans simultaneously [2,3-f] [1,3] benzodioxole -7- carbonyl] amino } -3,4- dihydro -2H-1- chromene -2-
Base] hexamethylene -1- formic acid；And
Trans- -4- [(2R, 4R) -4- [fluoro- 7- methyl -6, the 7- dihydro -2H- furans of (7R) -2,2- bis- simultaneously [2,3-f] [1,
3] benzodioxole -7- carbonyl] amino } -7- (trifluoromethoxy) -3,4- dihydro -2H-1- chromene -2- base] ring
Hexane -1- formic acid.
In one embodiment, therapeutic agent in addition is CFTR reinforcing agent.CFTR reinforcing agent enhances known CFTR regulator
The effect of (such as synergist and corrigent).The example of CFTR reinforcing agent is PTI130 and PTI-428.The example of reinforcing agent is also draped over one's shoulders
It is exposed in following publication: WO 2015138909 and WO 2015138934.
In one embodiment, therapeutic agent in addition is CFTR stabilizer.CFTR stabilizer enhancing corrigent, correction
The stability of agent/synergist or the CFTR through correcting of other one or more CFTR regulator combined treatments.CFTR stabilizer
Example be cavosonstat (N91115).The example of stabilizer is also disclosed in following publication: WO 2012048181.
In one embodiment, therapeutic agent in addition is the active medicament for reducing Epithelial sodium channel blocking agent (ENaC),
The reduction is directly to lead to the increased protease of ENaC activity (such as serine by blocking channel or indirectly by adjusting
Protease, channel activating protease enzyme) carry out.The example of such medicament includes camostat (camostat) (trypsase
Sample protease inhibitors), QAU145,552-02, GS-9411, INO-4995, Aerolytic, amiloride and VX-371.Drop
The low active other medicament of Epithelial sodium channel blocking agent (ENaC) can be in such as PCT Publication WO 2009074575 and WO
It is found in 2013043720 and U.S. Patent number US8999976.
In one embodiment, ENaC inhibitor is VX-371.
In one embodiment, ENaC inhibitor is SPX-101 (S18).
In one embodiment, the present invention provide comprising the compounds of this invention or its pharmaceutically acceptable salt and one kind or
The pharmaceutical composition of a variety of other therapeutic agents.In a specific embodiment, these other therapeutic agents are selected from the group, should
Group is made up of: CFTR regulator and CFTR reinforcing agent.In another embodiment, therapeutic agent in addition is that CFTR is adjusted
Agent.In one embodiment, the present invention provide comprising the compounds of this invention or its pharmaceutically acceptable salt, a kind of synergist,
And the pharmaceutical composition of one or more other corrigents.
The invention further relates to another comprising one or more the compound of the present invention and/or salt and optionally one or more
The kit of outer therapeutic agent.
The invention further relates to the compound of the present invention, salt, composition and/or kit be with or without it is one or more another
The method used in the case where outer therapeutic agent, such as adjust CF transmembrane conductance and adjust (CFTR) albumen, and control
Treat by adjust CF transmembrane conductance adjust the medicable disease of (CFTR) albumen (including cystic fibrosis, drying it is comprehensive
Simulator sickness, pancreatic insufficiency, chronic obstructive pulmonary disease and chronic obstructive airway disease).
Chemical synthesis program
It summarizes
The starting material that the compounds of this invention can be easy to get certainly is prepared using following conventional method and program.It should recognize
Know, is providing typical or preferred process conditions (that is, reaction temperature, time, the molar ratio of reactant, solvent, pressure
Power etc.) place, unless separately explaining, other process conditions also be can be used.Optimum reaction condition can be with used specific anti-
It answers object or solvent and changes, but these conditions can be determined by those skilled in the art by conventional optimum procedure.
In addition, as understood by those skilled in the art, it may be necessary to which Conventional protecting groups are to prevent certain functional groups from occurring
Undesirable reaction.The selection of suitable protecting group and protection and de-protected appropraite condition to particular functional group is ability
(the Protective Groups in Organic Synthesis Third Edition [guarantor in organic synthesis known to domain
Protect the group third edition]；Greene, T W and Wuts, P G M, editor；Willie international scientific publishing company (Wiley-
Interscience): New York, 1991).
Following method is presented in detail to prepare the compounds of this invention defined above and comparison example.The compounds of this invention
It can be prepared by organic synthesis field technical staff from known or commercially available starting material and reagent.
Unless otherwise specified, all reagents be all commercial level and in the case where not being further purified by
It uses as former state.Commercial anhydrous solvent is used for the reaction carried out under an inert atmosphere.Unless otherwise specified, every other situation
Under all use SILVER REAGENT solvent.Column chromatography is carried out on silica gel 60 (35-70 μm).It is (thick using the silica gel F-254 plate of precoating
Degree is 0.25mm) implement thin-layered chromatography.Microwave heating is usedInitiator carries out.
NMR spectra is recorded on Bruker Advance 300 or 400NMR spectrometer (300MHz).1H NMR spectra
Chemical shift (δ ppm) is relative to for interior target tetramethylsilane (δ ppm 0.00) or residual solvent peak (i.e. CHCl appropriate3
(δ ppm 7.27)) parts per million (ppm) report.With unimodal (s), bimodal (d), three peaks (t), quartet (q), quintet
(quin), multiplet (m) and broad peak (br) provide multiplicity.
Electron spray MS is obtained on being coupled to the mass spectrometric Waters Acquity UPLC system of Waters SQD or SQD2
Spectrum.Use is with lower prop: 1.7 μm of C18 of Waters Acquity UPLC BEH, 2.1mm ID x 50mm L or Waters
Acquity UPLC BEH C181.7 μm, 2.1mm ID x 30mm L.These methods use acetonitrile/H2O gradient (acetonitrile and H2O
Contain 0.1% formic acid or 0.05%NH4OH)。
For the compound purified by preparative scale chromatography, XBridge is usedTMPreparative guard column (C18 19 ×
5 μm of 10mm, water generation company (Waters)) and XBridgeTM(5 μm of C18 30x100mm, water generation is public for Prep OBD column
Department) and 0.1% formic acid (A) and acetonitrile (B) in water gradient, flow velocity be 50mL/ minutes.Alternatively, in guard column
With the ladder for using 0.1% diethylamine (A) in water and acetonitrile (B) that flow velocity is 50mL/ minutes on the same reference document of column
Degree.After elution, solvent is removed under vacuum to provide desciccate.
Separation and the mapping that racemic mixture is carried out in 2690 system of WatersAlliance detected with UV are different
The measurement of structure body purity.Use is with lower prop:IA (4.6x250mm, 5 μm).Use following solvent: isopropanol and heptan
Alkane.
Reverse phase purification process
Trifluoroacetic acid method
Sample is existed by preparative HPLCC8(2)5umAXIATMColumn (30mm ×
It is purified on 75mm).The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are 50mL/ minutes (0-1.0
Minute 5%A, 1.0-8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minute 100%A, 11.5-12.0 minutes linear ladders
Spend 95%-5%A).
Preparative LC/MS method TFA6
Sample is existed by Reverse phase preparative HPLCC8(2)5umAXIATMColumn (50mm ×
It is purified on 21.2mm).The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are 40mL/ minutes (0-
0.5 minute 15%A, 0.5-8.0 minutes linear gradient 15%-100%A, 8.0-9.0 minute 100%A, 7.0-8.9 minutes
100%A, 9.0-9.1 minutes linear gradient 100%-15%A, 9.1-10 minute 15%A).Using the purification system of customization,
By being formed with lower module: Gilson 305 and 306 is pumped；806 manometric module of Gilson；155 detector of Gilson UV/Vis；
Gilson 506C interface box；Gilson FC204 fraction collector device；The active separator of Agilent G1968D；Thermo MSQ
Plus mass spectrograph.The system is by Thermo Xcalibur 2.0.7 software and uses Microsoft Visual Basic
The combination of the custom application program of 6.0 internal compositions is controlled.
Preparative LC/MS method TFA7
Sample is existed by Reverse phase preparative HPLCC8(2)5umAXIATMColumn (50mm ×
It is purified on 21.2mm).The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are 40mL/ minutes (0-
0.5 minute 25%A, 0.5-8.0 minutes linear gradient 25%-100%A, 8.0-9.0 minute 100%A, 7.0-8.9 minutes
100%A, 9.0-9.1 minutes linear gradient 100%-25%A, 9.1-10 minute 25%A).Using the purification system of customization,
By being formed with lower module: Gilson 305 and 306 is pumped；806 manometric module of Gilson；155 detector of Gilson UV/Vis；
Gilson 506C interface box；Gilson FC204 fraction collector device；The active separator of Agilent G1968D；Thermo MSQ
Plus mass spectrograph.The system is by Thermo Xcalibur 2.0.7 software and uses Microsoft Visual Basic
The combination of the custom application program of 6.0 internal compositions is controlled.
Preparative LC/MS method TFA8
Sample is existed by Reverse phase preparative HPLCC8(2)5umAXIATMColumn (50mm ×
It is purified on 21.2mm).The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are 40mL/ minutes (0-
0.5 minute 35%A, 0.5-8.0 minutes linear gradient 35%-100%A, 8.0-9.0 minute 100%A, 7.0-8.9 minutes
100%A, 9.0-9.1 minutes linear gradient 100%-35%A, 9.1-10 minute 35%A).Using the purification system of customization,
By being formed with lower module: Gilson 305 and 306 is pumped；806 manometric module of Gilson；155 detector of Gilson UV/Vis；
Gilson 506C interface box；Gilson FC204 fraction collector device；The active separator of Agilent G1968D；Thermo MSQ
Plus mass spectrograph.The system is by Thermo Xcalibur 2.0.7 software and uses Microsoft Visual Basic
The combination of the custom application program of 6.0 internal compositions is controlled.
Preparative LC/MS method TFA10
Sample is existed by Reverse phase preparative HPLCC8(2)5umAXIATMColumn (50mm ×
It is purified on 21.2mm).The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are 30mL/ minutes (0-
0.2 minute 5%A, 0.2-3.0 minutes linear gradient 5%-100%A, 4.1-4.5 minute 100%-5%A, 4.5-5.0 minutes
5%A).Using the purification system of customization, by being formed with lower module: Gilson 305 and 306 is pumped；Gilson 806 surveys pressing mold
Block；155 detector of Gilson UV/Vis；Gilson506C interface box；Gilson FC204 fraction collector device；Agilent
The active separator of G1968D；Thermo MSQ Plus mass spectrograph.The system by Thermo Xcalibur 2.0.7 software and
It is controlled using the combination of the custom application program of 6.0 internal composition of Microsoft Visual Basic.
Preparative LC/MS method AA6
Sample is existed by Reverse phase preparative HPLCC8(2)5umAXIATMColumn (50mm ×
It is purified on 21.2mm).The gradient of 0.1% ammonium acetate (B) using acetonitrile (A) and in water, flow velocity are 40mL/ minutes (0-0.5
Minute 15%A, 0.5-8.0 minutes linear gradient 15%-100%A, 8.0-9.0 minute 100%A, 7.0-8.9 minutes 100%A,
9.0-9.1 minutes linear gradient 100%-15%A, 9.1-10 minute 15%A).Using the purification system of customization, by with lower die
Block composition: Gilson 305 and 306 is pumped；806 manometric module of Gilson；155 detector of Gilson UV/Vis；Gilson
506C interface box；Gilson FC204 fraction collector device；The active separator of Agilent G1968D；Thermo MSQ Plus matter
Spectrometer.The system is by Thermo Xcalibur 2.0.7 software and using inside Microsoft Visual Basic 6.0
The combination for the custom application program write is controlled.
Preparative LC/MS method AA7
Sample is existed by Reverse phase preparative HPLCC8(2)5umAXIATMColumn (50mm ×
It is purified on 21.2mm).The gradient of 0.1% ammonium acetate (B) using acetonitrile (A) and in water, flow velocity are 40mL/ minutes (0-0.5
Minute 25%A, 0.5-8.0 minutes linear gradient 25%-100%A, 8.0-9.0 minute 100%A, 7.0-8.9 minutes 100%A,
9.0-9.1 minutes linear gradient 100%-25%A, 9.1-10 minute 25%A).Using the purification system of customization, by with lower die
Block composition: Gilson 305 and 306 is pumped；806 manometric module of Gilson；155 detector of Gilson UV/Vis；Gilson
506C interface box；Gilson FC204 fraction collector device；The active separator of Agilent G1968D；Thermo MSQ Plus matter
Spectrometer.The system is by Thermo Xcalibur 2.0.7 software and using inside Microsoft Visual Basic 6.0
The combination for the custom application program write is controlled.
Preparative LC/MS method AA8
Sample is existed by Reverse phase preparative HPLCC8(2)5umAXIATMColumn (50mm ×
It is purified on 21.2mm).The gradient of 0.1% ammonium acetate (B) using acetonitrile (A) and in water, flow velocity are 40mL/ minutes (0-0.5
Minute 35%A, 0.5-8.0 minutes linear gradient 35%-100%A, 8.0-9.0 minute 100%A, 7.0-8.9 minutes 100%A,
9.0-9.1 minutes linear gradient 100%-35%A, 9.1-10 minute 35%A).Using the purification system of customization, by with lower die
Block composition: Gilson 305 and 306 is pumped；806 manometric module of Gilson；155 detector of Gilson UV/Vis；Gilson
506C interface box；Gilson FC204 fraction collector device；The active separator of Agilent G1968D；Thermo MSQ Plus matter
Spectrometer.The system is by Thermo Xcalibur 2.0.7 software and using inside Microsoft Visual Basic 6.0
The combination for the custom application program write is controlled.
Reverse phase purifying, ammonium acetate method
Sample is existed by preparative HPLCC8(2)5umAXIATMColumn (30mm ×
It is purified on 75mm).The gradient of 10mM ammonium acetate (B) using acetonitrile (A) and in water, flow velocity are that (0-1.0 divided in 50mL/ minutes
5%A, 1.0-8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minute 100%A of clock, 11.5-12.0 minutes linear gradients
95%-5%A).
Preparative HPLC purifying, ammonium carbonate method
Gradient increased to 70%B (25.0mL/ minutes flow velocitys) from 40% in 9.0 minutes.Mobile phase A is water (0.01%
NH3)+10mm(NH4HCO3), Mobile phase B is HPLC grades of acetonitriles.Column for chromatography is X-bridge Prep C18 10um
OBD, 19*250mm.Detection method is diode array (DAD) and Evaporative light scattering detector (ELSD) and anionic/cationic
Electrospray ionisation.
Buffer for reduction amination
The slow of reduction amination pH=4 is used for by preparing 36 grams of sodium acetates and 48 grams of acetic acids in 900mL methanol
The buffer of fliud flushing.
In some cases, based on the eluting order and/or activity about existing analog, it is arbitrarily designated final compound
Spatial chemistry.
The list of abbreviation used in experimental section:
The compounds of this invention is synthetically prepared
Scheme
The compound of present disclosure, the synthetic schemes and method may be better understood in conjunction with following synthetic schemes and method
Illustrating can be with the means of prepare compound.The compound of present disclosure can be prepared by various synthesis programs.Representative program
It is shown in but is not limited in scheme 1-7.
Scheme 1
As shown in scheme 1, the core compound with formula (2) can be prepared from the compound with formula (1).In alkali (example
11 carbon -7- alkene of such as, but not limited to, 1,8- diazabicylo [5.4.0], triethylamine or potassium carbonate) in the presence of, in solvent (example
Such as, but not limited to, toluene or tetrahydrofuran) in, lithium bromide can be used first, then use (E) -3,3- dimethyl -1- nitro butyl- 1-
Alkene processing has compound (the wherein R of formula (1)AUsually C1-C6Alkyl and R5It is as described herein), there is formula to provide
(2) racemic mixture of compound.The reaction usually carries out at reduced temperature (such as -78 DEG C), then with aqueous
Saturated ammonium chloride quenching.
Alternatively, in molecular sieve and alkali (11 carbon -7- alkene of such as, but not limited to 1,8- diazabicylo [5.4.0], three
Ethamine or potassium carbonate) in the presence of, in solvent (such as, but not limited to toluene or tetrahydrofuran), acetyl group (oxo) can be used
Silver processing has the compound of formula (1) and mixture (the wherein R of (E) -3,3- dimethyl -1- nitro but-1-eneAUsually C1-
C6Alkyl and R5It is as described herein), to provide the racemic mixture of the core compound with formula (2).The reaction usually exists
It carries out in ice bath, be then heated to room temperature and quenched with aqueous saturated ammonium chloride.
Scheme 2
As shown in scheme 2, the core compound with formula (3) and (4) can be prepared from the compound with formula (1).?
Under inert gas (such as, but not limited to argon gas or nitrogen), can there will be compound (the wherein R of formula (1)AUsually C1-C6Alkane
Base and R5It is as described herein) it is added to (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -
4,5- dihydro-oxazole -2- bases) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron and copper trifluoromethanesulfcomposite (I)
Dimer then adds (E) -3,3- dimethyl-in the mixture of the preparation in solvent (such as, but not limited to tetrahydrofuran)
1- nitro but-1-ene and alkali (such as, but not limited to potassium tert-butoxide), to provide the core compound with formula (3) and (4).The reaction
Usually carried out at reduced temperature (such as, but not limited to 0 DEG C).Core compound (3) and (4) can be used as mixture acquisition, or
Person can be separated by precipitating or chromatography.Core compound (3) is usually main isomer.
Scheme 3
As shown in Scheme 3, the compound with formula (11) can be prepared from the compound with formula (3).With formula (5)
Carboxylic acid can be coupled with the amine core with formula (3), with provide have formula (7) compound.The known mixing from carboxylic acid and amine
Object generates, and there is the example of the condition of compound of formula (7) including but not limited to add coupling agent, and the coupling agent is for example but unlimited
In the chloro- N of 1-, N, 2- trimethyl propyl- 1- alkene -1- amine (Ghosez reagent), N- (3- dimethylaminopropyl)-N '-ethyl carbon two
Imines or 1- (3- dimethylaminopropyl) -3- ethyl carbodiimide (EDC, EDAC or EDCI) or corresponding hydrochloride, 1,3-
Dicyclohexylcarbodiimide (DCC), bis- (2- oxo -3- oxazolidinyl) phosphonic chlorides (BOPCl), N- [(dimethylamino) -1H-
1,2,3-triazoles simultaneously-[4,5-b] pyridine -1- methylene]-N- methyl methylamine hexafluorophosphate N-oxide or 2- (7- azepine
Benzotriazole -1- base)-N, N, N ', N '-tetramethylurea hexafluorophosphate or 1- [bis- (dimethylamino) methylene] -1H-1,
2,3- triazols [4,5-b] pyridine 3- aoxidizes hexafluorophosphate (HATU), O- (benzotriazole -1- base)-N, N, N ', N '-four
Methylurea tetrafluoroborate (TBTU), 2- (1H- benzo [d] [1,2,3] triazol-1-yl) -1,1,3,3- tetramethyl isourea
Hexafluorophosphate (V) (HBTU) and 2,4,6- tripropyls -1,3,5,2,4,6- trioxa triphosphane, 2,4,6- trioxideCoupling agent can be used as solid, solution or to support the reagent of resin-bonded to add with solid.It is auxiliary in addition to coupling agent
Co-coupling agent can promote coupling reaction.Include but is not limited to commonly used in the ancillary coupling agent of coupling reaction: 4- (dimethylamino
Base) pyridine (DMAP), 1- hydroxyl -7- azepine benzotriazole (HOAT) and I-hydroxybenzotriazole (HOBT).The reaction can appoint
Selection of land carries out in the presence of alkali (such as, but not limited to triethylamine, n,N-diisopropylethylamine or pyridine).Coupling reaction can be
It is carried out in solvent, these solvents are such as, but not limited to tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, two
Methyl sulfoxide, methylene chloride and ethyl acetate.Reaction can be carried out in environment temperature or heating.Heating can routine or microwave
Irradiation is completed.
Alternatively, can by with thionyl chloride, PCl3、PCl5, cyanuric chloride or oxalyl chloride reaction will have formula (5)
Carboxylic acid be converted to the corresponding acyl chlorides with formula (6).N, N- dimethyl methyl can be used with thionyl chloride and reacting for oxalyl chloride
The amide catalysis in solvent (such as methylene chloride) at ambient temperature.The resulting acyl chlorides with formula (6) (or commercially available has
The acyl chlorides of formula (6)) it then can be with the core amine with formula (3) optionally in alkali (such as tertiary amine base, such as, but not limited to triethylamine
Or n,N-diisopropylethylamine) or aromatic base (such as pyridine) in the presence of at room temperature or in solvent (such as methylene chloride) plus
Heat is reacted, to provide the compound with formula (7).
It is that the compound with formula (8) can be by increasing by the Nitro group reduction in the compound with formula (7)
At a temperature of with the zinc in acetic acid handle the former to complete.The reaction usually in solvent (such as, but not limited to ethyl acetate) into
Row.
Alternatively, with formula (8) compound can by catalyst (such as, but not limited toNickel) exist
It is lower with hydrogen treat to there is the compound of formula (7) to prepare.The reaction is usually in solvent (such as, but not limited to water, tetrahydrofuran
Or mixtures thereof) in carry out at ambient temperature.
To have formula (8) compound reduction amination be the compound with formula (10) can by reducing agent (such as
But it is not limited to sodium cyanoborohydride or sodium triacetoxy borohydride) in the presence of, it is completed with the aldehyde reaction with formula (9),
Middle R4BIt is the R as being directed to formula (I)4The ring.The reaction can be in the presence of acetic acid or zinc chloride (II) in sodium acetate/acetic acid
It carries out in buffer, and is usually carried out at ambient temperature in solvent (such as, but not limited to methanol or dichloroethanes).
Ester with formula (10) can hydrolyze that (it is formula to provide the acid with formula (11) in hydroxide aqueous solution
(I) representative).The reaction usually carries out in solvent (such as, but not limited to or mixtures thereof methanol, tetrahydrofuran), and can
To be carried out under environment temperature or raised temperature.
Scheme 4
As shown in Scheme 4, the compound with formula (11) can be prepared from the compound with formula (4A).To with formula
The pyrrolidines nitrogen of the compound of (4A) is protected to provide and have the compound of formula (12) can be by with two dimethyl dicarbonate fourths
Ester handles the former to complete.The reaction usually carries out in solvent (such as, but not limited to tetrahydrofuran) at elevated temperatures.
It is that the compound with formula (13) can be by rising by the Nitro group reduction in the compound with formula (12)
The former is handled to complete with the zinc in acetic acid at a temperature of high.The reaction is usually in solvent (such as, but not limited to ethyl acetate)
It carries out.
Alternatively, with formula (13) compound can by catalyst (such as, but not limited toNickel) it deposits
With hydrogen treat there is the compound of formula (12) to prepare lower.The reaction is usually in solvent (such as, but not limited to water, tetrahydro furan
Or mixtures thereof mutter) in carry out at ambient temperature.
To have formula (13) compound reduction amination be the compound with formula (14) can by reducing agent (such as
But it is not limited to sodium cyanoborohydride) in the presence of, it is completed with the aldehyde reaction with formula (9), wherein R4BIt is as R4Described
Ring.The reaction can carry out in sodium acetate/acetate buffer in the presence of acetic acid or zinc chloride (II), and usually in solvent
It is carried out at ambient temperature in (such as, but not limited to methanol).
BOC blocking group in the compound for having formula (14) is gone to divided by offer there is the compound of formula (15) can lead to
It crosses and handles the former with sour (such as, but not limited to trifluoroacetic acid) to complete.The reaction is usually in solvent (such as, but not limited to dichloro
Methane) in carry out at ambient temperature.
Carboxylic acid with formula (5) can have the compound of formula (10) with offer with the amine coupling with formula (15).It is known
It includes but is not limited to add coupling agent that generating from the mixture of carboxylic acid and amine, which has the example of the condition of compound of formula (10), should
Coupling agent is such as, but not limited to N- (3- dimethylaminopropyl)-N '-ethyl carbodiimide or 1- (3- dimethylaminopropyl)-
3- ethyl carbodiimide (EDC, EDAC or EDCI) or corresponding hydrochloride, 1,3- dicyclohexylcarbodiimide (DCC), bis- (2-
Oxo -3- oxazolidinyl) phosphonic chloride (BOPCl), N- [(dimethylamino) -1H-1,2,3- triazols-[4,5-b] pyridine -1-
Methylene]-N- methyl methylamine hexafluorophosphate N-oxide or 2- (7- azepine benzo triazol-1-yl)-N, N, N ', N '-four
Methylurea hexafluorophosphate or 1- [bis- (dimethylamino) methylene] -1H-1,2,3- triazols [4,5-b] pyridine 3- oxygen
Change hexafluorophosphate (HATU), O- (benzotriazole -1- base)-N, N, N ', N '-tetramethylurea tetrafluoroborate (TBTU), 2-
(1H- benzo [d] [1,2,3] triazol-1-yl) -1,1,3,3- tetramethyl isourea hexafluorophosphate (V) (HBTU) and 2,4,6-
Tripropyl -1,3,5,2,4,6- trioxa triphosphane, 2,4,6- trioxideCoupling agent can be used as solid, solution
Or to support the reagent of resin-bonded to add with solid.In addition to coupling agent, ancillary coupling agent can promote coupling reaction.Usually use
Include but is not limited in the ancillary coupling agent of coupling reaction: 4- (dimethylamino) pyridine (DMAP), 1- hydroxyl -7- azepine benzo
Triazole (HOAT) and I-hydroxybenzotriazole (HOBT).The reaction can be optionally in alkali (such as, but not limited to triethylamine, N, N-
Diisopropylethylamine or pyridine) in the presence of carry out.Coupling reaction can carry out in a solvent, these solvents are such as, but not limited to four
Hydrogen furans, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide, methylene chloride and ethyl acetate.Reaction
It can be carried out in environment temperature or heating.Heating can routine or microwave irradiation completion.
Alternatively, can by with thionyl chloride, PCl3、PCl5, cyanuric chloride or oxalyl chloride reaction will have formula (5)
Carboxylic acid be converted to the corresponding acyl chlorides with formula (6).N, N- dimethyl methyl can be used with thionyl chloride and reacting for oxalyl chloride
The amide catalysis in solvent (such as methylene chloride) at ambient temperature.The resulting acyl chlorides with formula (6) (or commercially available has
The acyl chlorides of formula (6)) it then can be with the core amine with formula (15) optionally in alkali (such as tertiary amine base, such as, but not limited to three second
Amine or n,N-diisopropylethylamine) or aromatic base (such as pyridine) in the presence of at room temperature or in solvent (such as methylene chloride)
Heating is reacted, to provide the compound with formula (10).
Ester with formula (10) can hydrolyze that (it is formula to provide the acid with formula (11) in hydroxide aqueous solution
(I) representative).The reaction usually carries out in solvent (such as, but not limited to or mixtures thereof methanol, tetrahydrofuran), and can
To be carried out under environment temperature or raised temperature.
Scheme 5
As shown in scheme 5, the compound with formula (11) can be prepared from the compound with formula (4A).To with formula
The pyrrolidines nitrogen of the compound of (4A) is protected to provide and have the compound of formula (27) can be by saturation NaHCO3Water
The former is handled to complete with allyl chloroformate in the presence of solution.The reaction is usually in solvent (such as, but not limited to toluene)
It carries out at ambient temperature.
It is that the compound with formula (28) can be by rising by the Nitro group reduction in the compound with formula (27)
The former is handled to complete with the zinc in acetic acid at a temperature of high.The reaction is usually in solvent (such as, but not limited to ethyl acetate)
It carries out.
Alternatively, with formula (28) compound can by catalyst (such as, but not limited toNickel) it deposits
With hydrogen treat there is the compound of formula (27) to prepare lower.The reaction is usually in solvent (such as, but not limited to water, tetrahydro furan
Or mixtures thereof mutter) in carry out at ambient temperature.
Allyl-based protection group in the compound for having formula (29) is gone to have the compound of formula (15) can divided by offer
By the way that with 1,3- dimethyl pyrimidine -2,4,6 (1H, 3H, 5H)-triketones handle the former in the presence of tetrakis triphenylphosphine palladium (0)
To complete.The reaction is usually in environment temperature in solvent (such as, but not limited to or mixtures thereof ethyl acetate, methylene chloride)
Lower progress.
Carboxylic acid with formula (5) can have the compound of formula (10) with offer with the amine coupling with formula (15).It is known
It includes but is not limited to add coupling agent that generating from the mixture of carboxylic acid and amine, which has the example of the condition of compound of formula (10), should
Coupling agent is such as, but not limited to N- (3- dimethylaminopropyl)-N '-ethyl carbodiimide or 1- (3- dimethylaminopropyl)-
3- ethyl carbodiimide (EDC, EDAC or EDCI) or corresponding hydrochloride, 1,3- dicyclohexylcarbodiimide (DCC), bis- (2-
Oxo -3- oxazolidinyl) phosphonic chloride (BOPCl), N- [(dimethylamino) -1H-1,2,3- triazols-[4,5-b] pyridine -1-
Methylene]-N- methyl methylamine hexafluorophosphate N-oxide or 2- (7- azepine benzo triazol-1-yl)-N, N, N ', N '-four
Methylurea hexafluorophosphate or 1- [bis- (dimethylamino) methylene] -1H-1,2,3- triazols [4,5-b] pyridine 3- oxygen
Change hexafluorophosphate (HATU), O- (benzotriazole -1- base)-N, N, N ', N '-tetramethylurea tetrafluoroborate (TBTU), 2-
(1H- benzo [d] [1,2,3] triazol-1-yl) -1,1,3,3- tetramethyl isourea hexafluorophosphate (V) (HBTU) and 2,4,6-
Tripropyl -1,3,5,2,4,6- trioxa triphosphane, 2,4,6- trioxideCoupling agent can be used as solid, solution
Or to support the reagent of resin-bonded to add with solid.In addition to coupling agent, ancillary coupling agent can promote coupling reaction.Usually use
Include but is not limited in the ancillary coupling agent of coupling reaction: 4- (dimethylamino) pyridine (DMAP), 1- hydroxyl -7- azepine benzo
Triazole (HOAT) and I-hydroxybenzotriazole (HOBT).The reaction can be optionally in alkali (such as, but not limited to triethylamine, N, N-
Diisopropylethylamine or pyridine) in the presence of carry out.Coupling reaction can carry out in a solvent, these solvents are such as, but not limited to four
Hydrogen furans, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide, methylene chloride and ethyl acetate.Reaction
It can be carried out in environment temperature or heating.Heating can routine or microwave irradiation completion.
Alternatively, can by with thionyl chloride, PCl3、PCl5, cyanuric chloride or oxalyl chloride reaction will have formula (5)
Carboxylic acid be converted to the corresponding acyl chlorides with formula (6).N, N- dimethyl methyl can be used with thionyl chloride and reacting for oxalyl chloride
The amide catalysis in solvent (such as methylene chloride) at ambient temperature.The resulting acyl chlorides with formula (6) (or commercially available has
The acyl chlorides of formula (6)) it then can be with the core amine with formula (15) optionally in alkali (such as tertiary amine base, such as, but not limited to three second
Amine or n,N-diisopropylethylamine) or aromatic base (such as pyridine) in the presence of at room temperature or in solvent (such as methylene chloride)
Heating is reacted, to provide the compound with formula (10).
Ester with formula (10) can hydrolyze that (it is formula to provide the acid with formula (11) in hydroxide aqueous solution
(I) representative).The reaction usually carries out in solvent (such as, but not limited to or mixtures thereof methanol, tetrahydrofuran), and can
To be carried out under environment temperature or raised temperature.
Scheme 6
Scheme 6, which describes, makes R4The example of the diversified method of substituent group on the aromatic ring (Ar) of group.It can be such as in side
Preparation described in case 3 or 4 has the compound of formula (16), and wherein X is I, Br, Cl or fluoroform sulphonate and Ar is aryl
Or heteroaryl.It can be by making the compound (wherein X is I, Br, Cl or fluoroform sulphonate) with formula (16) and there is formula
(17) boronic acid compounds (wherein R9It is (or borate equivalent) as described herein) well known by persons skilled in the art
With can be reacted under widely available Suzuki coupling condition in the literature, to prepare the compound with formula (18).The reaction
It usually requires to use alkali and catalyst.The example of alkali includes but is not limited to potassium carbonate, potassium tert-butoxide, sodium carbonate, cesium carbonate and fluorine
Change caesium.The example of catalyst includes but is not limited to tetrakis triphenylphosphine palladium (0), [1,1 '-bis- (diphenylphosphino) ferrocene] two
Chlorine palladium (II) methylene chloride, bis- (triphenylphosphine) palladium chlorides (II) and tris(dibenzylideneacetone) dipalladium (0).The reaction
It can be in solvent (such as, but not limited to water, dioxanes, 1,2- dimethoxy-ethane, n,N-Dimethylformamide, toluene, ethyl alcohol, four
Or mixtures thereof hydrogen furans etc.) in carry out.The reaction can be under environment temperature or raised temperature, and optionally in microwave
It is carried out in furnace.Ester with formula (18) can be hydrolyzed in hydroxide aqueous solution to provide compound (its with formula (19)
For the representative of formula (I)).The reaction usually carries out in solvent (such as, but not limited to or mixtures thereof methanol, tetrahydrofuran), and
And it can be carried out under environment temperature or raised temperature.Can by the compound that makes there are formula (16) (wherein X be I, Br,
Cl or fluoroform sulphonate) with formula (20) organic zinc compound (wherein R9It is as described herein) in art technology
Personnel are known and can react under widely available root bank coupling condition in the literature, to prepare the chemical combination with formula (18)
Object.The reaction is usually required using palladium or Raney nickel.The example of catalyst includes but is not limited to dichloro [4,5- bis- chloro- 1,3-
Bis- (2,6- bis- -3- amyl phenyl) imidazoles -2- subunits] (3- chloropyridine base) palladium (II) (PEPPSI-IPentCl), four (triphenyls
Phosphine) nickel (0), tetrakis triphenylphosphine palladium (0), bis- (triphenylphosphine) palladium chlorides (II), [1,1 '-bis- (diphenylphosphinos) two cyclopentadienyl
Iron] dichloro palladium (II) methylene chloride, tris(dibenzylideneacetone) dipalladium (0) and acid chloride (II).The reaction can be in solvent
(such as, but not limited to water, dioxanes, 1-Methyl-2-Pyrrolidone, n,N-dimethylacetamide, 1,2- dimethoxy-ethane, N,
Or mixtures thereof dinethylformamide, toluene, ethyl alcohol, tetrahydrofuran etc.) in carry out.The reaction can be in environment temperature or liter
At a temperature of high, and carry out optionally in micro-wave oven.Ester with formula (18) can hydrolyze in hydroxide aqueous solution
There is the compound (it is the representative of formula (I)) of formula (19) to provide.The reaction usually solvent (such as, but not limited to methanol,
Or mixtures thereof tetrahydrofuran) in carry out, and can be carried out under environment temperature or raised temperature.It can be by making to have
The compound (wherein X is I, Br, Cl or fluoroform sulphonate) of formula (16) and amine compounds (the wherein R with formula (22)9It is H
Or as described herein) well known by persons skilled in the art and can widely available Buchwald-Hart in the literature
It is reacted under Vichy (Buchwald-Hartwig) amination conditions, to prepare the compound with formula (22).The reaction is usual
It needs using alkali, catalyst and optionally ligand.The example of alkali includes but is not limited to potassium carbonate, potassium tert-butoxide, the tert-butyl alcohol
Sodium, sodium carbonate, cesium carbonate and cesium fluoride.The example of catalyst includes but is not limited to dichloro [4,5- bis- chloro- 1,3- bis- (2,6- bis--
3- amyl phenyl) imidazoles -2- subunit] (3- chloropyridine base) palladium (II) (PEPPSI-IPentCl), chloro- (2- dicyclohexyl phosphino- -
2 ', 6 '-diisopropoxy -1,1 '-xenyl) [2- (2- amino-ethyl) phenyl] palladium (II)-methyl t-butyl ether adduct
(RuPhos ring palladium), four (triphenylphosphine) nickel (0), tetrakis triphenylphosphine palladium (0), bis- (triphenylphosphine) palladium chlorides (II), [1,
1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) methylene chloride, tris(dibenzylideneacetone) dipalladium (0) and acid chloride
(II).The example of optional ligand include but is not limited to BINAP (2,2 '-bis- (diphenylphosphino) -1,1 '-dinaphthyl), DPPF (1,
1 '-bis- (diphenylphosphino) ferrocene) and Xantphos (4,5- bis- (diphenylphosphino) -9,9- dimethylxanthenes).The reaction
It can be in solvent (such as, but not limited to water, dioxanes, 1-Methyl-2-Pyrrolidone, n,N-dimethylacetamide, dimethoxy second
Or mixtures thereof alkane, n,N-Dimethylformamide, toluene, ethyl alcohol, tetrahydrofuran etc.) in carry out.The reaction can be in environment temperature
Under degree or raised temperature, and carry out optionally in micro-wave oven.Ester with formula (22) can be in hydroxide aqueous solution
Middle hydrolysis is to provide the compound with formula (23) (it is the representative of formula (I)).The reaction usually solvent (such as, but not limited to
Or mixtures thereof methanol, tetrahydrofuran) in carry out, and can be carried out under environment temperature or raised temperature.
Scheme 7
Scheme 7 shows the compound for having formula (26) from the compound preparation with formula (8).It can be by making with formula
(24) compound (wherein X is I, Br, Cl or fluoroform sulphonate, and Ar is aryl or heteroaryl) with there are formula (8)
Amine it is well known by persons skilled in the art and can in the literature under widely available Buchwald-Hartwig amination conditions into
Row reaction, to prepare the compound with formula (25).The reaction is usually required using alkali, catalyst and optionally ligand.Alkali
Example include but is not limited to potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, cesium carbonate and cesium fluoride.The example of catalyst
Including but not limited to dichloro [4,5- bis- chloro- bis- (2, the 6- bis- -3- amyl phenyl) imidazoles -2- subunits of 1,3-] (3- chloropyridine base) palladium
(II) (PEPPSI-IPentCl), chloro- (2- dicyclohexyl phosphino- -2 ', 6 '-diisopropoxy -1,1 '-xenyl) [2- (2- ammonia
Base ethyl) phenyl] palladium (II)-methyl t-butyl ether adduct (RuPhos ring palladium), four (triphenylphosphine) nickel (0), four (triphens
Base phosphine) palladium (0), bis- (triphenylphosphine) palladium chlorides (II), [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) dichloro
Methane, tris(dibenzylideneacetone) dipalladium (0) and acid chloride (II).The example of optional ligand includes but is not limited to BINAP
(2,2 '-bis- (diphenylphosphino) -1,1 '-dinaphthyl), DPPF (1,1 '-bis- (diphenylphosphino) ferrocene) and Xantphos
(4,5- bis- (diphenylphosphino) -9,9- dimethylxanthenes).The reaction can be in solvent (such as, but not limited to water, dioxanes, 1- first
Base -2-Pyrrolidone, n,N-dimethylacetamide, dimethoxy-ethane, n,N-Dimethylformamide, toluene, ethyl alcohol, tetrahydro furan
Or mixtures thereof mutter etc.) in carry out.The reaction can be under environment temperature or raised temperature, and optionally in micro-wave oven
It carries out.
Ester with formula (25) can hydrolyze that (it is to provide the compound with formula (26) in hydroxide aqueous solution
The representative of formula (I)).The reaction usually carries out in solvent (such as, but not limited to or mixtures thereof methanol, tetrahydrofuran), and
It can be carried out under environment temperature or raised temperature.
Example
Catalyst and intermediate synthesis
Catalyst 1
(2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2- base)
Amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron
The method for being used to prepare chiral ligand is adapted from Yan, X.-X., Peng, Q., Zhang, Y., Zhang, K., Hong,
W., Hou, X.-L.and Wu, Y.-D., Angew.Chem., Int.Ed. [applied chemistry English international version] 2006,451979-
1983。
By amyl- 2, the 4- diene -1- base of ring (3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2- base) amyl- 2,4- diene-of ring
1- yl) iron (515mg, 1.733mmol) is dissolved in 2- methyltetrahydrofuran (17mL).Acquired solution is bathed in acetone-dry ice
In be cooled to -78 DEG C, add tetramethylethylenediamine (0.340mL, 2.253mmol), be then added dropwise s-butyl lithium (1.485mL,
2.080mmol), < -70 DEG C of internal temperature are kept.After stirring 30 minutes, reaction mixture is disposably used to bis- (3,5- bis- (three
Methyl fluoride) phenyl) chlorine phosphine (1110mg, 2.253mmol) handled.After -78 DEG C are stirred 1 hour, by reaction flask from bath
Middle taking-up is simultaneously warmed to environment temperature, is then diluted with 20mL methyl tertiary butyl ether(MTBE), and sudden with 10mL saturated aqueous ammonium chloride
It goes out.These layers are separated, and organic layer 10mL is saturated aqueous ammonium chloride and 10mL salt water washing, is dried over sodium sulfate, filters
And it is concentrated.By rough material via chromatography, with isocratic 93: 7 heptane on 80g silicagel column: methyl tertiary butyl ether elute 20 minutes into
Row purifying, to provide the title compound of 920mg.1H NMR (300MHz, CDCl3) δ ppm 0.86 (d, J=6.6Hz, 3H),
0.92 (d, J=6.3Hz, 3H), 1.69-1.77 (m, 1H), 3.49-3.50 (m, 1H), 3.73-3.81 (m, 1H), 3.96 (t, J
=7.8Hz, 1H), 4.21-4.27 (m, 6H), 4.46-4.48 (m, 1H), 5.00-5.01 (m, 1H), 7.65 (d, J=6.3Hz,
2H), 7.80 (s, 1H), 7.89 (d, J=6.0Hz, 2H), 7.93 (s, 1H)；MS(ESI+)m/z 754.0(M+H)+。
Intermediate 1
(E)-3,3Dimethyl-1Nitro butyl-1Alkene
Intermediate 1A
3,3- dimethyl -1- nitro butyl- 2- alcohol
30 points are stirred in 0 DEG C in dry tetrahydrofuran (140mL) to lithium aluminium hydride reduction (0.881g, 23.22mmol)
Nitromethane (70.9g, 1161mmol) is added dropwise in the slurry of clock.After 30 minutes, special valeral (20g, 232mmol) is added dropwise.It will mix
It closes object to stir 5 hours at 0 DEG C, and is quenched with the aqueous HCl of 1N.Reaction mixture is poured into water, CH is used2Cl2(2x250mL)
Extraction, is washed with salt water (2x200mL), through Na2SO4Be dried, filtered and concentrated with provide title compound (17g, 107mmol,
46.3% yield).LC-MS(ESI-) m/z=146.7 (M-H)-。
Intermediate 1B
(E)-3,3Dimethyl-1Nitro butyl-1Alkene
By solution of 3, the 3- dimethyl -1- nitro butyl- 2- alcohol (10g, 67.9mmol) in methylene chloride (100mL) in N2
Under be cooled to -10 DEG C, with 2,2,2- trifluoroacetic anhydride (15.70g, 74.7mmol) handle, -15 DEG C stir 5 minutes, with three second
Amine (20.84mL, 149mmol) is handled dropwise, keeps bath at -15 DEG C during addition.Mixture is stirred 3 hours at 0 DEG C, is used
It is saturated NH4Cl aqueous solution (300mL) processing, and stir 5 minutes.Separate CH2Cl2Layer and by water layer CH2Cl2(2 × 150mL) extraction
It takes.By combined CH2Cl2Dry (the Na of layer2SO4), filter and be concentrated.Rough material is passed through into column chromatography (ethyl acetate/petroleum
Ether=1/200) purifying, to provide title compound (6.8g, 48.4mmol, 71.3% yield).1H NMR (400MHz, CDCl3)
δ ppm 7.19 (d, J=13.2Hz, 1H), 6.83 (d, J=13.6Hz, 1H), 1.09 (s, 9H).
Intermediate 2
2- (3- formoxyl -4- methoxyphenyl) -2- methyl propionitrile
Intermediate 2A
((the bromo- 2- methoxy-benzyl of 5-) oxygroup) (tert-butyl) dimethylsilane
(the bromo- 2- methoxyphenyl of 5-) methanol (1.89g, 8.71mmol) is dissolved in the methylene chloride of 25mL.Add miaow
Azoles (0.711g, 10.45mmol) then adds tert-butyldimethylsilyl chloride compound (1.378g, 9.14mmol).In room
After lower stirring 15 minutes of temperature, complete to react by thin-layered chromatography.Add CH3OH (1mL) simultaneously stirs reaction mixture 5 minutes
And it is washed with the aqueous HCl of 1M (3x 15mL) and salt water (15mL), and be dried over sodium sulfate.After filtering, filtrate is concentrated to provide mark
Compound is inscribed, it can be used without other purifying.1H NMR (400MHz, chloroform-d) δ ppm 7.60 (dd, J=2.5,
1.2Hz, 1H), 7.33 (dd, J=8.7,2.6Hz, 1H), 6.71 (d, J=8.6Hz, 1H), 4.74 (d, J=1.0Hz, 2H),
3.82 (d, J=1.1Hz, 3H), 0.99 (s, 9H), 0.15 (s, 6H)；MS (ESI+) m/z=329.8 (M+H)+。
Intermediate 2B
2- (3- (((t-butyldimethylsilyl) oxygroup) methyl) -4- methoxyphenyl) -2- methyl propionitrile
Loading intermediate 2A (2.7g, the 8.15mmol), 2 in 250-mL round-bottomed flask, 2 '-bis- (diphenylphosphino) -1,
1 '-dinaphthyl (BINAP, 0.507g, 0.815mmol) and diacetoxy palladium (0.183g, 0.815mmol).Add toluene
(20mL), and by suspension N2Stream injection 15 minutes.Bis- (trimethyl silyls) is packed into individual 100-mL flask
The solution of amide sodium (NaHMDS, 0.6M in toluene, 20.37mL, 12.22mmol), and be added dropwise isobutyronitrile (0.841mL,
9.37mmol).It is stirring after ten minutes, HMDS solution is being transferred in 250-mL reaction flask via syringe.Gained is hanged
Supernatant liquid is heated to 100 DEG C and is kept for 30 minutes, is cooled to environment temperature at this time, is saturated aqueous ammonium chloride with 30mL and dilutes, and
It is extracted with methyl tertiary butyl ether(MTBE) (3x20mL).Combined organic extract is concentrated, and via purified by flash chromatography, in 40g
With 0: 100 to 20: 80 ethyl acetate on silicagel column: heptane elutes 20 minutes, to provide 2.0g title compound.1H NMR
(400MHz, chloroform-d) δ ppm 7.50 (dd, J=2.6,1.4Hz, 1H), 7.28 (dd, J=8.5,2.7Hz, 1H), 6.74 (d,
J=8.5Hz, 1H), 4.69 (s, 1H), 3.75 (s, 1H), 1.64 (s, 7H), 0.90 (s, 1H), 0.05 (s, 1H)；MS(ESI+)
M/z=188.0 (M-OTBS)+.
Intermediate 2C
2- (3- (hydroxymethyl) -4- methoxyphenyl) -2- methyl propionitrile
Intermediate 2B (2g, 6.26mmol) is dissolved in CH3In OH (10mL), and (3M is in ring by addition HCl at ambient temperature
In amyl methyl ether, 0.209mL, 0.626mmol).Solution becomes very shallow yellow, continues stirring 10 minutes, such as passes through at this time
What thin-layer chromatographic analysis was measured has occurred complete deprotection.Reaction mixture is concentrated in a vacuum, to provide the mark of 1.15g
Compound is inscribed, subsequent oxidation reaction is directly used in.
Intermediate 2D
2- (3- formoxyl -4- methoxyphenyl) -2- methyl propionitrile
Intermediate 2C (600mg, 2.92mmol) is dissolved in methylene chloride (14.6mL), and adds Dai Si-Martin
(Dess-Martin) iodine alkane (1.49g, 3.51mmol) is crossed.Reaction mixture is stirred 1 hour at ambient temperature, is led at this time
It crosses thin-layer chromatographic analysis and shows its completion.By reaction mixture with methyl tertiary butyl ether(MTBE) (30mL) dilute, and be saturated aqueous sulfur
Sodium thiosulfate and saturation aqueous sodium bicarbonate (each 15mL) quenching, are then stirred at room temperature 15 minutes.Organic materials is extracted
To in methyl tertiary butyl ether(MTBE) (2x30mL), and combined extract is washed with salt water (20mL), is dried over sodium sulfate, filtering, dense
Contracting can be used without other purifying, to provide title compound (570mg).1H NMR (400MHz, chloroform-d) δ ppm
10.47 (s, 1H), 7.86 (d, J=2.7Hz, 1H), 7.75 (dd, J=8.8,2.7Hz, 1H), 7.03 (d, J=8.8Hz),
3.96 (s, 3H), 1.72 (s, 6H)；MS (ESI+) m/z=220.8 (M+NH4)+。
Intermediate 3
2Methoxyl group-5-(1(methoxy) cyclopropyl) benzaldehyde
Intermediate 3A
(1- (4- methoxyphenyl) cyclopropyl) methanol
Methyl 1- (4- methoxyphenyl) cyclopropane formic ether (2.2g, 10.7mmol) is dissolved in the tetrahydrofuran of 50mL
In.After being cooled to 5 DEG C of < in ice-water bath, LiAlH is slowly added via syringe4(2M in tetrahydrofuran, 5.33mL,
10.7mmol), 10 DEG C of internal temperature < are kept.After the completion of addition, LC-MS shows completely consuming for starting material.Reaction is used
1mL CH3OH quenching, is then diluted with methyl tertiary butyl ether(MTBE), and stir 5 minutes together with the aqueous HCl of 1M (100mL).By these
Layer separation, and organic layer is washed with salt water (20mL), it is then condensed into residue, residue is loaded on 40g silicagel column,
With 0: 100 to 20: 80 ethyl acetate: heptane elutes 20 minutes, to provide (1- (4- methoxyphenyl) cyclopropyl) first of 1.6g
Alcohol.1H NMR (400MHz, chloroform-d) δ ppm 7.29 (d, J=8.8Hz, 2H), 6.85 (d, J=8.8Hz, 2H), 3.79 (s,
3H), 3.62 (s, 2H), 0.82 (ddd, J=6.7,2.2,1.1Hz, 4H)；MS (ESI+) m/z=161.1 (M-OH)+.
Intermediate 3B
1- methoxyl group -4- (1- (methoxy) cyclopropyl) benzene
Intermediate 3A (1.45g, 8.14mmol) is dissolved in n,N-Dimethylformamide (16.27mL).It is being cooled to < 5
After DEG C, add sodium hydride (60% in the oil, 0.423g, 10.58mmol), and acquired solution is stirred to 15 points at ambient temperature
Clock, then disposably addition iodomethane (1.017mL, 16.27mmol).It is small that reaction mixture is stirred to 16 at ambient temperature
When, it is then diluted with 50mL water, and extracted with methyl tertiary butyl ether(MTBE) (3x30mL).By combined organic extract water
The washing of (4x20mL) and salt water (20mL), is then dried over sodium sulfate, and filters and is concentrated to provide title compound, by its without
In addition (1.66g) can be used in purifying.
Intermediate 3C
The bromo- 1- methoxyl group -4- of 2- (1- (methoxy) cyclopropyl) benzene
Intermediate 3B (1.66g, 8.63mmol) is dissolved in CH3In CN (21.59mL), and disposably add N- bromine succinyl
Imines (1.690g, 9.50mmol).Reaction is stirred 1 hour at ambient temperature, its completion is shown by LC-MS at this time.It will
Reaction content is concentrated into about 5mL in a vacuum, then will be diluted with the methyl tertiary butyl ether(MTBE) of 50mL.By gained suspension water
The washing of (3x20mL) and salt water (20mL), is then dried over sodium sulfate, and filters and is concentrated to provide title compound, by its without
In addition purifying can be used.
Intermediate 3D
2- methoxyl group -5- (1- (methoxy) cyclopropyl) benzaldehyde
Intermediate 3C (2.25g, 8.30mmol) is dissolved in the tetrahydrofuran of 40mL, and solution is bathed in dry ice-propanone
In be cooled to < -70 DEG C.It is added dropwise n-BuLi (1.51M in heptane, 3.65mL, 9.13mmol) via syringe, in holding
< -65 DEG C of portion's temperature.Same temperature stirring after ten minutes, disposably add n,N-Dimethylformamide (1.928mL,
24.89mmol), and reaction mixture is made to be warmed to environment temperature.Thin-layered chromatography and LC-MS show starting aryl bromide
Conversion completely.Reaction mixture is diluted with methyl tertiary butyl ether(MTBE) (10mL) and is quenched with aqueous ammonium chloride (20mL) is saturated.It will
The separation of these layers, and organic layer is concentrated in a vacuum, then via purified by flash chromatography, with 0: 100 on 80g silicagel column
To 15: 85 ethyl acetate: heptane elutes 20 minutes, to provide 720mg title compound.1H NMR (400MHz, chloroform-d) δ
Ppm 10.44 (s, 1H), 7.77 (d, J=2.5Hz, 1H), 7.57 (dd, J=8.6,2.5Hz, 1H), 6.92 (d, J=8.6Hz,
1H), 3.91 (s, 3H), 3.44 (s, 2H), 3.30 (s, 3H), 0.85 (br s, 4H).MS (ESI+) m/z=221.0 (M+H)+。
Intermediate 4
3- (bromomethyl) -5- cyclobutyl -2- methoxypyridine
Intermediate 4A
5- cyclobutyl -2- methoxynicotinate
By the bromo- 2- methoxynicotinate (8g, 32.5mmol) of 5- and PdCl2(dppf) ([1,1 '-bis- (diphenylphosphines
Base) ferrocene] dichloro palladium (II), 0.595g, 0.813mmol) it is suspended in and uses N in the bottle of 20-mL nitrogen purging2Spray
It penetrates in 10 minutes tetrahydrofurans (163mL).Be added dropwise cyclobutyl zinc bromide (II) (0.5M in tetrahydrofuran, 85mL,
Trade solution 42.3mmol), and allow to react and stir 16 hours at ambient temperature.Reaction mixture is saturated aqueous chlorine
Change ammonium (50mL) quenching, and these layers are separated.Organic layer is washed with the aqueous ammonium chloride (2x25mL) of saturation and salt water (50mL)
Wash, be then dried over sodium sulfate, filter, be concentrated and via purified by flash chromatography, with 0: 100 to 10 on 120g silicagel column:
90 ethyl acetate: heptane elutes 20 minutes, to provide the title compound of 6.15g.1H NMR (400MHz, chloroform-d) δ ppm
8.20-8.11 (s, 1H), 8.06-7.98 (s, 1H), 4.02 (s, 3H), 3.91 (s, 3H), 3.57-3.41 (m, 1H), 2.43-
2.26 (m, 2H), 2.21-1.97 (m, 3H), 1.89 (dddd, J=11.6,8.9,7.0,1.4Hz, 1H)；MS (ESI+) m/z=
222.2(M+H)+。
Intermediate 4B
(5- cyclobutyl -2- methoxypyridine -3- base) methanol
Intermediate 4A (6.15g, 27.8mmol) is dissolved in tetrahydrofuran (69.5mL), and solution is cooled to 5 DEG C of <.
Through 5 minutes dropwise addition LiAlH4(2M in tetrahydrofuran, 9.73mL, 19.46mmol) solution is kept for 10 DEG C of internal temperature <.Add
After the completion of adding, LC-MS is shown complete conversion as desired alcohol.It is slowly added saturation Rochelle salt (sodium potassium tartrate tetrahydrate) (75mL)
To quench reaction, then the reaction is diluted with methyl tertiary butyl ether(MTBE) (150mL).Mixture is stirred 60 points in environment temperature
Clock.These layers are separated, and water layer is extracted with methyl tertiary butyl ether(MTBE) (3x25mL).Combined organic extract is aqueous with 1M
NaOH (50mL) and salt water (50mL) washing, are dried over sodium sulfate, filter, and be concentrated in a vacuum to provide title compound,
It can be used without other purifying.1H NMR (400MHz, chloroform-d) δ ppm 7.90 (d, J=2.4Hz, 1H), 7.49
(dd, J=2.5,0.9Hz, 1H), 4.64 (d, J=4.7Hz, 2H), 3.96 (d, J=1.0Hz, 3H), 3.48 (p, J=8.6Hz,
1H), 2.51 (s, 1H), 2.42-2.23 (m, 2H), 2.23-1.95 (m, 3H), 1.95-1.83 (m, 1H)；MS (ESI+) m/z=
194.0(M+H)+。
Intermediate 4C
3- (bromomethyl) -5- cyclobutyl -2- methoxypyridine
Intermediate 4B (5.2g, 26.9mmol) is dissolved in methylene chloride (135mL), and add triphenylphosphine (8.82g,
33.6mmol).Acquired solution is cooled to 5 DEG C of < in ice-water bath, and NBS (N- bromine succinyl is added batch-wise within 3-5 minutes
Imines) (5.99g, 33.6mmol), kept for 20 DEG C of internal temperature <.Reaction mixture is stirred 20 minutes in same bath, this
When LC-MS show complete conversion.It adds silica gel (50g), and suspension is concentrated in a vacuum.Rough material is poured into containing 3
In the disposable sinter funnel (500mL) of the silica of inch heptane filling, with heptane wash flask.By desired product
With 20: 80 methyl tertiary butyl ether(MTBE)s: heptane elutes, to provide the title compound of 4.88g.1H NMR (501MHz, chloroform-d) δ
Ppm 7.94 (dd, J=2.3,0.8Hz, 1H), 7.49 (dd, J=2.4,0.6Hz, 1H), 4.49 (s, 2H), 3.99 (s, 3H),
3.47 (ddddd, J=9.2,8.6,7.9,7.2,0.7Hz, 1H), 2.41-2.25 (m, 2H), 2.18-1.95 (m, 3H), 1.95-
1.82 (m, 1H)；MS (ESI+) m/z=255.9 (M+H)+。
Intermediate 5
2- methoxyl group -5- (1- methyl-cyclobutyl) benzaldehyde
Intermediate 5A
1- (4- methoxyphenyl) cyclobutanol
(4- methoxyphenyl) magnesium bromide (56.9mL, 28.5mmol, 0.5M are in tetrahydrofuran) solution is cooled to -78
DEG C, cyclobutanone (2.239mL, 30.0mmol) then is added dropwise via syringe.After the completion of addition, mixture is warmed to environment temperature
It spends and uses aqueous ammonium chloride (10mL) quenching of saturation.Mixture is diluted with methyl tertiary butyl ether(MTBE) (20mL), and these layers are divided
From.Organic layer is washed with the aqueous ammonium chloride (20mL) of saturation and salt water (20mL), is then dried over sodium sulfate, is filtered and be concentrated
To provide title compound, (5.3g) is can be used into without other purifying in it.1H NMR (400MHz, chloroform-d) δ ppm
7.45 (d, J=8.8Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 3.84 (s, 3H), 2.57 (dddd, J=12.4,6.5,2.8,
1.7Hz, 2H), 2.43-2.27 (m, 2H), 2.18-1.89 (m, 2H), 1.76-1.60 (m, 1H).
Intermediate 5B
1- methoxyl group -4- (1- methyl-cyclobutyl) benzene
Intermediate 5A (3g, 16.83mmol) is dissolved in methylene chloride (84mL), and by acquired solution in dry ice-propanone
- 78 DEG C are cooled in bath.Titanium tetrachloride (IV) (pure, 3.69mL, 33.7mmol) is added via syringe, and solution is existed
It is stirred 1 hour under same temperature, it is molten to be then slowly added 1M of zinc methide (50.5mL, the 50.5mmol) solution in heptane
Liquid.After the completion of addition, reaction flask is warmed to environment temperature, is then poured into beaker in 300mL ice, while acutely being stirred
It mixes.Gained suspension methylene chloride (100mL) is diluted and stirred 5 minutes, is then filtered by diatomite and uses salt water
(50mL) washs organic layer.Organic layer is dried over sodium sulfate, is filtered, and is concentrated to provide title compound (2.97g), by it
It can be used without other purifying.1H NMR (500MHz, chloroform-d) δ ppm 7.14 (d, J=8.7Hz, 2H), 6.90 (d, J
=8.7Hz, 2H), 3.84 (s, 3H), 2.40 (qd, J=9.4,8.9,2.1Hz, 2H), 2.21-2.04 (m, 3H), 1.92-1.81
(m, 1H), 1.48 (s, 3H).
Intermediate 5C
2- methoxyl group -5- (1- methyl-cyclobutyl) benzaldehyde
Intermediate 5B (3g, 17.02mmol) is dissolved in the methylene chloride of 110mL, and by acquired solution in ice-brine bath
In be cooled to 0 DEG C of <.After adding dichloro (methoxyl group) methane (1.70mL, 18.7mmol), through 2 minutes dropwise addition titanium tetrachlorides
The solution of (2065mL, 18.72mmol) in 10mL methylene chloride is kept for 5 DEG C of internal temperature <.15 minutes at the same temperature
Afterwards, thin-layered chromatography shows to convert completely.Gained mixture 40mL water is quenched, these layers are separated, and organic layer is dense
It contracts and is loaded on 80g silicagel column, with 0: 100 to 15: 85 ethyl acetate: heptane elutes 20 minutes, to provide the title of 2.05g
Compound.1H NMR (400MHz, chloroform-d) δ ppm 10.49 (d.J=1.0Hz, 1H), 7.67 (dd, J=2.6,0.9Hz,
1H), 7.40 (ddd, J=8.6,2.6,1.0Hz, 1H), 6.96 (d, J=8.6Hz, 1H), 3.94 (d, J=0.9Hz, 3H),
2.37 (td, J=10.3,9.7,7.2Hz, 2H), 2.19-2.01 (m, 3H), 1.89-1.73 (m, 1H), 1.46 (s, 3H)；MS
(ESI+) m/z=205.1 (M+H)+。
Intermediate 6
5- (tert-butyl) -2- methoxyl group cigarette aldehyde
Intermediate 6A
(the bromo- 2- methoxypyridine -3- base of 5-) methanol
The bromo- 2- methoxyl group cigarette aldehyde (2g, 9.26mmol) of 5- is suspended in CH3In OH (40mL), and mixture is cooled to 0
℃.Disposable addition sodium borohydride (0.350g, 9.26mmol), causes to be bubbled.Reaction mixture is stirred 15 minutes at 0 DEG C,
Then flask is taken out from ice bath and allows to be stirred at room temperature 2 hours.Reaction mixture is concentrated in a vacuum, and will be thick
Material is absorbed in methyl tertiary butyl ether(MTBE) and saturation NaHCO3In aqueous solution.These are mutually separated, and by organic layer through Na2SO4It is dry
It is dry, filtering, and be concentrated in a vacuum to provide title compound (1.876g, 93% yield).1H NMR (400MHz, CDCl3)δ
Ppm 8.15 (d, J=2.5Hz, 1H), 7.75 (d, J=2.4Hz, 1H), 4.66 (d, J=6.2Hz, 2H), 3.99 (s, 3H),
2.15 (t, J=6.3Hz, 1H)；MS(DCI+)m/z 217.8(M+H)。
Intermediate 6B
The bromo- 3- of 5- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxypyridine
By (the bromo- 2- methoxypyridine -3- base of 5-) methanol (1.876g, 8.60mmol), t-butyldimethylsilyl
Chloride (1.556g, 10.32mmol) and imidazoles (0.879g, 12.91mmol) are in CH2Cl2It is stirred at room temperature in (35mL)
It mixes overnight.After this, the CH of 5mL is added3Reaction mixture is stirred at room temperature 10 minutes with quenching reaction by OH.It will mix
Close object CH2Cl2Dilution, and be saturated NaHCO3Aqueous solution washes twice, and is washed with brine primary.Organic solution is passed through
Na2SO4It dries, filters, and is concentrated to provide the bromo- 3- of title compound 5- (((t-butyldimethylsilyl) oxygroup) first
Base) -2- methoxypyridine (2.71g, 95% yield).1H NMR (400MHz, CDCl3) δ ppm 8.08 (dt, J=2.5,
0.9Hz, 1H), 7.81 (dt, J=2.5,1.2Hz, 1H), 4.65 (m, 2H), 3.93 (s, 3H), 0.93 (s, 9H), 0.14 (s,
6H)；MS(ESI+)m/z 332.0(M+H)。
Intermediate 6C
5- (tert-butyl) -3- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxypyridine
Into 2 neck round-bottom flask of 50mL add nickel chloride-dimethoxy-ethane adduct (0.033g, 0.150mmol) and
1,3- dicyclohexyl -1H- imidazoles -3- tetrafluoroborate (0.048g, 0.150mmol) then adds the bromo- 3- of 5- (((tertiary fourth
Base dimetylsilyl) oxygroup) methyl) -2- methoxypyridine (intermediate 6B, 0.500g, 1.505mmol) is in tetrahydrofuran
Solution in (6mL).It is backfilled seven times by system evacuation and with nitrogen, and the reaction is cooled to -10 DEG C.Tert-butyl chlorination is added dropwise
Magnesium (1M is in tetrahydrofuran) (3mL, 3.00mmol), and reaction is stirred 100 minutes at -10 DEG C.After this, by reaction ice
Piece quenches and allows to warm to room temperature.Mixture is poured into saturation NH4In Cl aqueous solution, and it is extracted with ethyl acetate three times.
Combined organic extract is washed with brine, through Na2SO4It dries, filters, and is concentrated in a vacuum.Silica gel chromatography is (with 0
Eluted to 10% ethyl acetate-heptane) provide title compound 236mg.Impure material is i.e. available without other purifying
In next step.1H NMR (400MHz, CDCl3) δ ppm 8.06 (m, 1H), 7.82 (m, 1H), 4.72 (s, 2H), 3.96 (s,
3H), 1.34 (s, 9H), 1.00 (s, 9H), 0.14 (s, 6H)；MS(ESI+)m/z 310.2(M+H)+。
Intermediate 6D
(5- (tert-butyl) -2- methoxypyridine -3- base) methanol
Impure material from intermediate 6C (236mg) is dissolved in tetrahydrofuran (7.6mL) and uses tetrabutyl ammonium fluoride
Trihydrate (1.20g, 3.81mmol) processing.The reaction is stirred at room temperature.After 4 hours, reaction mixture is poured into full
And NH4In the mixture of Cl aqueous solution and salt water.Mixture is extracted with ethyl acetate three times.Combined organic matter is passed through
Na2SO4It dries, filters, and is concentrated in a vacuum, to provide thick title compound, be directly entered it without further purification
In next reaction.MS(APCI+)m/z 196.2(M+H)。
Intermediate 6E
5- (tert-butyl) -2- methoxyl group cigarette aldehyde
Crude product from intermediate 6D (0.762mmol) is dissolved in CH2Cl2In (6mL), and solution is cooled to 0 DEG C.
4 crowdes of addition Dai Si-Martins are divided to cross iodine alkane (0.388g, 0.914mmol).Flask is taken out from ice bath and allows to stir at room temperature
It mixes.After 3 hours, reaction mixture 50mL methyl tertiary butyl ether(MTBE) is diluted, and be saturated Na with 50mL2S2O3Aqueous solution and 50mL
It is saturated NaHCO3Solution is vigorously stirred 5 minutes.Mixture is transferred in separatory funnel, these are mutually separated, and will be organic
Layer is washed with brine, through Na2SO4It dries, filters, and is concentrated in a vacuum.Silica gel chromatography is (with 0 to 20% ethyl acetate-heptan
Alkane elution) title compound 0.060g (41% yield) is provided.1H NMR (500MHz, DMSO-d6) δ ppm 10.24 (s, 1H),
8.53 (d, J=2.7Hz, 1H), 8.06 (d, J=2.8Hz, 1H), 3.99 (s, 3H), 1.31 (s, 9H)；MS(ESI+)m/z
194.0(M+H)+。
Intermediate 7
6- (tert-butyl) -3-Methoxy Pyridine formaldehyde
Intermediate 7A
(the bromo- 3-Methoxy Pyridine -2- base of 6-) methanol
The bromo- 3-Methoxy Pyridine formaldehyde (0.880g, 4.07mmol) of 6- is suspended in CH3In OH (20mL), and will mixing
Object is cooled to 0 DEG C.It adds sodium borohydride (0.154g, 4.07mmol), causes to be bubbled.Reaction mixture is stirred 15 points at 0 DEG C
Then flask is taken out from ice bath and allows to be stirred at room temperature 2 hours by clock.Reaction mixture is concentrated in a vacuum, and
Rough material is absorbed in methyl tertiary butyl ether(MTBE) and saturation NaHCO3In aqueous solution.These are mutually separated, and organic layer is passed through
Na2SO4It dries, filters, and is concentrated in a vacuum to provide title compound (0718g, 81% yield).1H NMR (501MHz,
CDCl3) δ ppm 8.15 (d, J=2.4Hz, 1H), 7.75 (m 1H), 4.66 (dt, J=6.3,0.7Hz, 2H), 2.16 (t, J=
6.3Hz, 1H)；MS(ESI+)m/z 218.0(M+H)+。
Intermediate 7B
The bromo- 2- of 6- (((t-butyldimethylsilyl) oxygroup) methyl) -3-Methoxy Pyridine
By (the bromo- 3-Methoxy Pyridine -2- base of 6-) methanol (0.718g, 3.29mmol), t-butyldimethylsilyl
Chloride (0.596g, 3.95mmol) and imidazoles (0.336g, 4.94mmol) are in CH2Cl2It is stirred at room temperature in (13mL)
Overnight.Then by reaction 3mL CH3OH quenching, and reaction mixture is stirred at room temperature 10 minutes.Mixture is used
CH2Cl2Dilution, and be saturated NaHCO3Aqueous solution washes twice, and is washed with brine primary.By organic solution through Na2SO4It is dry
It is dry, it filters and is concentrated in a vacuum, to provide title compound (0.997g, 91% yield).1H NMR (400MHz, CDCl3)δ
Ppm 7.34 (d, J=8.5Hz, 1H), 7.05 (d, J=8.5Hz, 1H), 4.80 (s, 2H), 3.84 (s, 3H), 0.92 (s, 9H),
0.12 (s, 6H).
Intermediate 7C
6- (tert-butyl) -2- (((t-butyldimethylsilyl) oxygroup) methyl) -3-Methoxy Pyridine
Nickel chloride-dimethoxy-ethane adduct (0.066g, 0.300mmol) is added into 2 neck round-bottom flask of 100mL
With 1,3- dicyclohexyl -1H- imidazoles -3- tetrafluoroborate (0.096g, 0.300mmol), the bromo- 2- (((uncle of 6- is then added
Butyldimethylsilyl) oxygroup) methyl) -3-Methoxy Pyridine (0997g, 300mmol) is in tetrahydrofuran (12mL)
Solution.It is backfilled seven times by system evacuation and with nitrogen, then the reaction is cooled to -10 DEG C, and tert-butyl magnesium chloride are added dropwise (1M exists
In tetrahydrofuran) (6.00mL, 6.00mmol).Reaction mixture is stirred 150 minutes at -10 DEG C.Then by reaction ice
Piece quenches and allows to warm to room temperature.Mixture is poured into saturation NH4In Cl aqueous solution, and it is extracted with ethyl acetate three times.
Combined organic extract is washed with brine, through Na2SO4It dries, filters, and is concentrated in a vacuum.Silica gel chromatography is (with 0
Eluted to 40% ethyl acetate-heptane) provide thick title compound, 0.356g, 38% yield.1H NMR (400MHz, CDCl3)δ
Ppm 7.18 (d, J=8.5Hz, 1H), 7.06 (d, J=8.5Hz, 1H), 4.86 (s, 2H), 3.82 (s, 3H), 1.35 (s, 9H),
0.92 (s, 9H), 0.10 (s, 6H)；MS(ESI+)m/z 310.1(M+H)+。
Intermediate 7D
(6- (tert-butyl) -3-Methoxy Pyridine -2- base) methanol
It will be in 6- (tert-butyl) -2- (((t-butyldimethylsilyl) oxygroup) first in tetrahydrofuran (11mL)
Base) -3-Methoxy Pyridine (0.356g, 1.150mmol) is at 4-butyl ammonium fluoride trihydrate (1.814g, 5.75mmol)
Reason, and reaction is stirred at room temperature overnight.Reaction mixture is poured into the saturation NH in separatory funnel4Cl aqueous solution and
In the mixture of saline solution, and mixture is extracted with ethyl acetate three times.By combined extract through Na2SO4It is dry, mistake
It filters and is concentrated in a vacuum.Material is set to be directly entered next step without further purification.MS(APCI+)m/z 196.3(M+
H)+。
Intermediate 7E
6- (tert-butyl) -3-Methoxy Pyridine formaldehyde
(6- (tert-butyl) -3-Methoxy Pyridine -2- base) methanol (0.225g, 1.15mmol) is dissolved in CH2Cl2(12mL) simultaneously
It is cooled to 0 DEG C.Dai Si-Martin is added batch-wise and crosses iodine alkane (0.585g, 1.380mmol), flask is taken out from ice bath, and allows
Mixture is stirred at room temperature.After 2 hours, reaction mixture 80mL methyl tertiary butyl ether(MTBE) is diluted, and is saturated with 80mL
Na2S2O3Aqueous solution and 80mL are saturated NaHCO3Solution processing.Mixture is vigorously stirred 5 minutes, is then transferred to mixture
In separatory funnel, and these are mutually separated.Organic layer is washed with brine, through Na2SO4It dries, filters, and dense in a vacuum
Contracting.Silica gel chromatography (being eluted with 0 to 50% ethyl acetate-heptane) provides title compound, 0.118g, 53% yield.1H
NMR (400MHz, CDCl3) δ ppm 10.23 (s, 1H), 7.53 (d, J=8.8Hz, 1H), 7.33 (d, J=8.9Hz, 1H),
3.95 (s, 3H), 1.39 (s, 9H)；MS(ESI+)m/z 194.1(M+H)+。
Intermediate 8
3- methoxyl group -6- (1- (trifluoromethyl) cyclopropyl) pyridine carboxaldehyde
By 3-Methoxy Pyridine formaldehyde (0.117g, 0.850mmol) and 1- (trifluoromethyl) cyclopropane -1- sulfinic acid sodium
(0.500g, 2.55mmol) is dissolved in diethyl carbonate (5.1mL) and water (3.4mL), and mixture is cooled to 0 DEG C.So
Tert-butyl hydroperoxide is added dropwise afterwards (70% is aqueous, 0.547g, 4.25mmol).Reaction is stirred 5 minutes in ice bath, is then existed
90 DEG C are heated 2 hours.After this, mixture is cooled to room temperature, with saturation Na2S2O3Aqueous solution (10mL) quenching, and use ethyl alcohol
(20mL) dilution.Mixture is concentrated in a vacuum, and resulting material is absorbed in 20%CH3In OH- ethyl acetate, and burning
It ties and is filtered on glass funnel by silicagel pad, use 10%CH3The elution of OH- ethyl acetate.Combined filtrate is concentrated in a vacuum,
And be purified by silica gel chromatography residue, it is eluted with 40% ethyl acetate-heptane to 100% ethyl acetate (gradient).It obtains
Obtain title compound, 0.0253g, 12% yield.1H NMR (400MHz, CDCl3) δ ppm 10.35 (s, 1H), 8.47 (s, 1H),
7.50 (s, 1H), 4.02 (s, 3H), 1.53 (m, 2H), 1.28 (m, 2H)；MS(ESI+)m/z 246.1(M+H)+。
Intermediate 9
3- methoxyl group -6- (trifluoromethyl) pyridine carboxaldehyde
By 3-Methoxy Pyridine formaldehyde (0.150g, 1.094mmol) and Sodium trifluoromethanesulfinate (0.500g,
It 3.20mmol) is dissolved in diethyl carbonate (6.6mL) and water (4.4mL), and mixture is cooled to 0 DEG C.Then tertiary fourth is added dropwise
Base hydrogen peroxide (70% is aqueous, 0.704g, 5.47mmol).Reaction is stirred 5 minutes in ice bath, then heats 90 at 90 DEG C
Minute.After this, by reaction saturation Na2S2O3Aqueous solution (10mL) quenching, is then diluted with ethyl alcohol (20mL).Reaction is mixed
It closes object to be concentrated in a vacuum, resulting material is then absorbed in 20%CH3In OH- ethyl acetate, and on a sintered glass funnel
It is filtered by silicagel pad, uses 10%CH3The elution of OH- ethyl acetate.Combined filtrate is concentrated in a vacuum.Residue is passed through
Silica gel chromatography is eluted with the gradient of 40% ethyl acetate-heptane to 100% ethyl acetate, titled to provide
Close object, 0.0245g, 11% yield.1H NMR (400MHz, CDCl3) δ ppm 10.28 (s, 1H), 7.89 (m, 1H), 7.56 (m,
1H), 4.07 (s, 3H)；MS(ESI+)m/z 206.1(M+H)+。
Intermediate 10
5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -2- methoxyl group cigarette aldehyde
Intermediate 10A
(the bromo- 2- methoxypyridine -3- base of 5-) methanol
The bromo- 2- methoxyl group cigarette aldehyde (2g, 9.26mmol) of 5- is suspended in CH3In OH (40mL), and mixture is cooled to 0
℃.Disposable addition sodium borohydride (0.350g, 9.26mmol), causes to be bubbled.Reaction mixture is stirred 15 minutes at 0 DEG C,
Then flask is taken out from ice bath and allows to be stirred at room temperature 2 hours.Reaction mixture is concentrated in a vacuum, and will be thick
Material is absorbed in methyl tertiary butyl ether(MTBE) and saturation NaHCO3In aqueous solution.These are mutually separated, and by organic layer through Na2SO4It is dry
It is dry, filtering, and be concentrated in a vacuum to provide title compound, 1.876g, 93% yield.1H NMR (400MHz, CDCl3)δ
Ppm 8.15 (d, J=2.5Hz, 1H), 7.75 (d, J=2.4Hz, 1H), 4.66 (d, J=6.2Hz, 2H), 3.99 (s, 3H),
2.15 (t, J=6.3Hz, 1H)；MS(DCI+)m/z 217.8(M+H)+。
Intermediate 10B
The bromo- 3- of 5- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxypyridine
By (the bromo- 2- methoxypyridine -3- base of 5-) methanol (1.876g, 8.60mmol), t-butyldimethylsilyl
Chloride (1.556g, 10.32mmol) and imidazoles (0.879g, 12.91mmol) are in CH2Cl2It is stirred at room temperature in (35mL)
It mixes overnight.After this, the CH of 5mL is added3Reaction mixture is stirred at room temperature 10 minutes with quenching reaction by OH.It will mix
Close object CH2Cl2Dilution, and be saturated NaHCO3Aqueous solution washes twice, and is washed with brine primary.Organic solution is passed through
Na2SO4It dries, filters, and is concentrated to provide title compound, 2.71g, 95% yield.1H NMR (400MHz, CDCl3)δppm
8.08 (dt, J=2.5,0.9Hz, 1H), 7.81 (dt, J=2.5,1.2Hz, 1H), 4.65 (m, 2H), 3.93 (s, 3H), 0.93
(s, 9H), 0.14 (s, 6H)；MS(ESI+)m/z 332.0(M+H)+。
Intermediate 10C
3- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxyl group -5- (propyl- 1- alkene -2- base) pyridine
By the bromo- 3- of 5- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxypyridine (0.500g,
The evil of 1.505mmol), 4,4,5,5- tetramethyl -2- (propyl- 1- alkene -2- base) -1,3,2- bis- ring pentaborane (0.329g,
1.956mmol) and Pd (PPh3)4(tetrakis triphenylphosphine palladium (0), 0.174g, 0.150mmol) with dioxanes (12mL) and
Solution processing of the potassium carbonate (0.416g, 3.01mmol) in water (3mL), and reaction mixture is heated overnight at 100 DEG C.This
Later, reaction mixture is diluted with ethyl acetate, and be washed with water three times, is washed with brine primary.Through Na2SO4Dry,
After filtering and being concentrated in a vacuum, rough material is subjected to chromatography on silica gel, 0 to 10% ethyl acetate-heptane of use elutes, with
Title compound 3- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxyl group -5- (propyl- 1- alkene -2- base) is provided
Pyridine (0.376g, 85% yield).1H NMR (500MHz, CDCl3) δ ppm 8.07 (m, 1H), 7.74 (m, 1H), 5.35 (m,
1H), 5.06 (m, 1H), 4.71 (m, 2H), 3.98 (s, 3H), 2.16 (s, 3H), 0.99 (s, 9H), 0.15 (s, 6H)；MS(ESI+)m/z 294.2(M+H)+。
Intermediate 10D
3- (((t-butyldimethylsilyl) oxygroup) methyl) -5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -2- methoxy
Yl pyridines
It will be in 3- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxyl group-in tetrahydrofuran (1.5mL)
5- (propyl- 1- alkene -2- base) pyridine (0.050g, 0.170mmol) then uses (fluoroform with sodium iodide (5.1mg, 0.034mmol)
Base) trimethyl silane (2M in tetrahydrofuran, 0.21mL, 0.426mmol) processing.Reaction mixture is vigorously stirred at 65 DEG C
3 hours.Reaction mixture is cooled to room temperature and uses saturation NH4Cl aqueous solution is handled with care, and by mixture methyl- tert fourth
Base ether extracts three times.By combined organic matter water and salt water washing, through Na2SO4It dries, filters, and is concentrated in a vacuum to mention
For title compound (75mg, quantitative), it is directly entered it without further purification in next reaction.1H NMR (400MHz,
CDCl3) δ ppm 7.99 (d, J=2.4Hz, 1H), 7.68 (m, 1H), 4.69 (m, 2H), 3.95 (s, 3H), 1.65 (m, 1H),
1.51 (s, 3H), 1.43 (m, 1H), 0.97 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H)；MS(ESI+)m/z 344.1(M+H)+。
Intermediate 10E
(5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -2- methoxypyridine -3- base) methanol
By 3- (((t-butyldimethylsilyl) oxygroup) methyl) -5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -2- first
Oxygroup pyridine (0.246g, 0.715mmol) and 4-butyl ammonium fluoride trihydrate (1.128g, 3.58mmol) are in tetrahydrofuran
It is stirred at room temperature overnight in (7mL).After this, mixture is poured into saturation NH4In the mixture of Cl aqueous solution and salt water,
And mixture is extracted with ethyl acetate three times.By combined organic matter through Na2SO4Dry, filter, and be concentrated in a vacuum with
Title compound is provided, is directly entered it without further purification in next reaction.MS(ESI+)m/z 230.3(M+H)+。
Intermediate 10F
5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -2- methoxyl group cigarette aldehyde
It will be in CH2Cl2(5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -2- methoxypyridine -3- base) methanol in (5mL)
(intermediate 10E, 0.164g, 0.715mmol) is cooled to 0 DEG C, and crosses iodine alkane (0.364g, 0.858mmol) point with Dai Si-Martin
Batch processing.After the completion of addition, reaction is removed from ice bath and allows to be stirred at room temperature 1 hour.Then by reaction mixture
Na is saturated with 85mL methyl tertiary butyl ether(MTBE), 85mL2S2O3Aqueous solution and 85mL are saturated NaHCO3Aqueous solution dilution.By mixture
It is vigorously stirred 5 minutes.Mixture is transferred in separatory funnel, these are mutually separated, and organic layer is washed with brine, is passed through
Na2SO4It dries, filters, and is concentrated in a vacuum.Gained thick residue is purified by silica gel chromatography, 0 to 50% acetic acid of use
Ethyl ester-heptane elution.Title compound, 0.097g, 60% yield are obtained through three steps.1H NMR (400MHz, CDCl3)δ
Ppm 10.37 (s, 1H), 8.35 (dd, J=2.6,0.8Hz, 1H), 8.07 (d, J=2.6Hz, 1H), 4.09 (s, 3H), 1.67
(m, 1H), 1.53 (m, 3H), 1.49 (m, 1H)；MS(APCI+)m/z 228.2(M+H)+。
Intermediate 11
The different cigarette aldehyde of 2- (tert-butyl) -5- methoxyl group
Intermediate 11A
The bromo- 4- of 2- (((t-butyldimethylsilyl) oxygroup) methyl) -5- methoxypyridine
By (the bromo- 5- methoxypyridine -4- base of 2-) methanol (Ali chemical company (Anichem)；0.500g,
2.293mmol), tert-butyldimethylsilyl chloride compound (TBDMS-Cl, 0.415g, 2.75mmol) and imidazoles
(0.234g, 3.44mmol) is in CH2Cl2It is stirred at room temperature in (10mL) 3 days.After this, by mixture CH2Cl2Dilution,
And with water and salt water washing.By organic layer through Na2SO4It dries, filters, and is concentrated in a vacuum bromo- to provide title compound 2-
4- (((t-butyldimethylsilyl) oxygroup) methyl) -5- methoxypyridine (0660g, 87% yield).1H NMR
(501MHz, CDCl3) δ ppm 792 (s, 1H), 758 (s, 1H), 472 (d, J=12Hz, 2H), 3.91 (s, 3H), 0.89 (s,
9H), 0.16 (s, 6H)；MS(ESI+)m/z 332.1(M+H)+。
Intermediate 11B
2- (tert-butyl) -4- (((t-butyldimethylsilyl) oxygroup) methyl) -5- methoxypyridine
Into 2 neck round-bottom flask of 100mL add nickel chloride dimethoxy-ethane adduct (0.044g, 0.199mmol) and
1,3- dicyclohexyl -1H- imidazoles -3- tetrafluoroborate (0.064g, 0.199mmol) then adds the bromo- 4- of 2- (((tertiary fourth
Base dimetylsilyl) oxygroup) methyl) -5- methoxypyridine (0.660g, 1.986mmol) is in tetrahydrofuran (8mL)
Solution.It is backfilled seven times by system evacuation and with nitrogen, and the reaction is cooled to -10 DEG C.Tert-butyl magnesium chloride is added dropwise, and (1M is four
In hydrogen furans) (4mL, 4mmol), and reaction is stirred 100 minutes at -10 DEG C.After this, reaction borneol is quenched and allowed
It warms to room temperature.Mixture is poured into saturation NH4In Cl aqueous solution, and it is extracted with ethyl acetate three times.By the organic of merging
Extract is washed with brine, through Na2SO4It dries, filters, and is concentrated in a vacuum.Silica gel chromatography is (with 5% to 50% acetic acid
Ethyl ester-heptane elution) provide title compound 2- (tert-butyl) -4- (((t-butyldimethylsilyl) oxygroup) methyl) -
5- methoxypyridine (0.178g, 29% yield).1H NMR (501MHz, CDCl3) δ ppm 814 (s, 1H), 7.55 (s, 1H),
4.76 (d, J=1.1Hz, 2H), 3.91 (s, 3H), 1.38 (s, 9H), 1.00 (s, 9H), 0.15 (s, 6H)；MS(ESI+)m/z
310.3(M+H)+。
Intermediate 11C
(2- (tert-butyl) -5- methoxypyridine -4- base) methanol
By 2- (tert-butyl) -4- (((t-butyldimethylsilyl) oxygroup) methyl) -5- methoxypyridine
(0.178g, 0.575mmol) and 4-butyl ammonium fluoride trihydrate (0.907g, 2.88mmol) in tetrahydrofuran (5mL)
It is stirred overnight at room temperature.After this, reaction mixture is poured into the aqueous NH of the saturation in separatory funnel4Cl and salt water it is mixed
It closes in object, and is extracted with ethyl acetate three times.By combined organic matter through Na2SO4It dries, filters, and is concentrated in a vacuum,
To provide thick title compound 328mg, it is directly entered it without further purification in next reaction.1H NMR (501MHz,
CDCl3) δ ppm 8.22 (s, 1H), 7.37 (s, 1H), 4.74 (s, 2H), 3.95 (s, 3H), 1.38 (s, 9H)；MS(ESI+)m/z
196.2(M+H)+。
Intermediate 11D
The different cigarette aldehyde of 2- (tert-butyl) -5- methoxyl group
It will be in CH2Cl2In (5mL) (2- (tert-butyl) -5- methoxypyridine -4- base) methanol (0.112g,
It is 0.575mmol) cooling in ice bath, iodine alkane (0.293g, 0.690mmol) then, which is crossed, with Dai Si-Martin handles in three batches.It will mix
It closes object to stir in ice bath 30 minutes, then take out flask from ice bath and is continuously stirred at room temperature overnight.It, will after this
Methyl tertiary butyl ether(MTBE), the saturation Na of each 70mL of reaction mixture2S2O3Aqueous solution and saturation NaHCO3Aqueous solution processing.It will
Mixture is vigorously stirred 10 minutes.Mixture is transferred in separatory funnel, these are mutually separated, and by organic layer salt water
Washing, through Na2SO4It dries, filters, and is concentrated in a vacuum.Silica gel chromatography (being eluted with 0 to 50% ethyl acetate-heptane) is given
The different cigarette aldehyde of title compound 2- (tert-butyl) -5- methoxyl group (0.040g, 36% yield) out；MS(APCI+)m/z 194.2(M+
H)+。
Intermediate 12
2- methoxyl group -5- (1,1,1- tri- fluoro- 2- methylpropane -2- base) benzaldehyde
Intermediate 12A
4- (1,1,1- tri- fluoro- 2- methylpropane -2- base) phenol
It will be in 4,4,5,5- tetramethyl -2- (4- (1,1, the 1- tri- fluoro- 2- methylpropane -2- in tetrahydrofuran (16mL)
Base) phenyl) -1,3,2- bis- dislike ring pentaborane (0.500g, 1.592mmol) about 3 DEG C (internal temperature) are cooled in ice bath.Drop
Adding sodium hydroxide (1M is aqueous) (2.6mL, 2.60mmol) is to keep reaction temperature at 4 DEG C or lower.Hydrogen peroxide (30% is added dropwise
It is aqueous) (0.2mL, 1.958mmol), cause reaction temperature to be increased to 13 DEG C.By the cold stirring of mixture 20 minutes, and it is warmed to room
Temperature simultaneously stirs 2 days.After this, mixture 5mL is saturated Na2S2O3Aqueous solution is handled and is vigorously stirred 30 minutes.Then it adds
HCl (1N, aqueous) is added to pH 4, and mixture is extracted with ethyl acetate three times.Combined extract is washed with brine,
And combined water-washing liquid is extracted with ethyl acetate once.By combined organic matter through Na2SO4It dries, filters and in vacuum
Middle concentration, to provide thick title compound 4- (1,1,1- tri- fluoro- 2- methylpropane -2- base) phenol, 698mg makes it without another
Outer purifying enters in next reaction.1H NMR (501MHz, CDCl3) δ ppm 7.38 (m, 2H), 6.85 (m, 2H), 5.53
(s, 1H), 1.57 (s, 6H).
Intermediate 12B
2- hydroxyl -5- (1,1,1- tri- fluoro- 2- methylpropane -2- base) benzaldehyde
Will in acetonitrile (8mL) 4- (1,1,1- tri- fluoro- 2- methylpropane -2- base) phenol (intermediate 12A,
1.592mmol) with paraformaldehyde (0.416g, 13.85mmol), magnesium chloride (0.243g, 2.55mmol) and triethylamine
(1.4mL, 10.04mmol) processing.Reaction is heated at 80 DEG C, is vigorously stirred 18 hours.It is after this, reaction mixture is cooling
It is handled to room temperature and with the aqueous HCl of 50mL 1M.By mixture CH2Cl2It is extracted twice (each 50mL).Combined organic matter is passed through
Na2SO4It dries, filters, and is concentrated in a vacuum, to provide thick title compound 391mg, keep it straight without other purifying
It taps into next reaction.1H NMR (400MHz, CDCl3) δ ppm 11.01 (s, 1H), 9.95 (s, 1H), 7.71-7.67 (m,
2H), 7.03 (d, J=8.7Hz, 1H), 1.27 (s, 6H).
Intermediate 12C
2- methoxyl group -5- (1,1,1- tri- fluoro- 2- methylpropane -2- base) benzaldehyde
It will be in 2- hydroxyl -5- (1,1,1- tri- fluoro- 2- methylpropane -2- base) benzene in n,N-Dimethylformamide (53mL)
Formaldehyde (intermediate 12B, 1.592mmol) potassium carbonate (0.330g, 2.388mmol) and iodomethane (0.15mL, 2.399mmol)
Processing, and mixture is vigorously mixed at room temperature for overnight.The mixture aqueous NaOH of 1N of 50mL is handled, and uses methyl- tert
Butyl ether (2x50mL) extraction.By combined organic matter water and salt water washing, through Na2SO4It dries, filters, and in a vacuum
Concentration.Silica gel chromatography (being eluted with 0 to 25% ethyl acetate-heptane) provides title compound 2- methoxyl group -5- (1,1,1- tri-
Fluoro- 2- methylpropane -2- base) benzaldehyde (through three steps, 0.209g, 53% yield).1H NMR (400MHz, CDCl3)δppm
10.48 (s, 1H), 7.96 (d, J=2.7Hz, 1H), 7.71 (ddq, J=8.8,2.7,0.9Hz, 1H), 7.01 (d, J=
8.8Hz, 1H), 3.96 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H).
Intermediate 13
6- cyclobutyl -2- methoxyl group cigarette aldehyde
Intermediate 13A
The bromo- 3- of 6- (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxypyridine
It will be in CH2Cl2The tertiary fourth of (the bromo- 2- methoxypyridine -3- base of 6-) methanol (1.0g, 4.59mmol) in (20mL)
Base dimethylsilylchloride (TBDMS-Cl, 0.829g, 5.50mmol) and imidazoles (0.468g, 6.88mmol) processing,
And reaction mixture is stirred at room temperature overnight.Then by mixture 5mL CH3OH is handled and is stirred a few minutes to quench
Remaining TBDMS-Cl.By mixture CH2Cl2Dilution, and be saturated NaHCO3Aqueous solution washes twice, and is washed with brine
Once.By organic layer through Na2SO4It dries, filters, and is concentrated in a vacuum, to provide the bromo- 3- (((tert-butyl of title compound 6-
Dimetylsilyl) oxygroup) methyl) -2- methoxypyridine (1.453g, 95% yield).
Intermediate 13B
3- (((t-butyldimethylsilyl) oxygroup) methyl) -6- cyclobutyl -2- methoxypyridine
By with the bromo- 3- of the 6- of toluene azeotropic drying (((t-butyldimethylsilyl) oxygroup) methyl) -2- methoxyl group
Pyridine (0.500g, 1.505mmol) is dissolved in tetrahydrofuran (15mL), and with dichloro [1,3- bis- (2,6- bis- -3- amyl phenyl)
Imidazoles -2- subunit] (3- chloropyridine base) palladium (II) (PEPPSI IPentCl, 0.129g, 0.150mmol) processing, then through several
Cyclobutyl zinc bromide (II) (0.5M is in tetrahydrofuran) (6.0mL, 3.0mmol) is added dropwise via syringe at room temperature in minute.
After 30 minutes, reaction mixture is dimmed at green-palm fibre-yellow in clear.Mixture is poured into saturation NH4In Cl aqueous solution,
And it is extracted with ethyl acetate three times.By combined organic matter through Na2SO4It dries, filters, and is concentrated in a vacuum, and will be thick residual
Excess is purified by silica gel chromatography, and 0 to 5% ethyl acetate-heptane of use elutes 15 minutes.By still impure title compound
3- (((t-butyldimethylsilyl) oxygroup) methyl) -6- cyclobutyl -2- methoxypyridine (473mg) is without further pure
Change i.e. in next reaction.1H NMR (400MHz, CDCl3) δ ppm 7.59 (m, 1H), 6.73 (m, 1H), 4.68 (s, 2H),
3.98 (s, 3H), 3.55 (p, J=8.6Hz, 1H), 2.42-2.22 (m, 4H), 2.07-1.93 (m, 1H), 1.96-1.85 (m,
1H), 0.96 (m, 9H), 0.12 (s, 6H)；MS(ESI+)m/z 308.2(M+H)+。
Intermediate 13C
(6- cyclobutyl -2- methoxypyridine -3- base) methanol
It will be in thick 3- (((t-butyldimethylsilyl) oxygroup) methyl) -6- ring fourth in tetrahydrofuran (15mL)
Base -2- methoxypyridine (intermediate 13B, 1.505mmol) is at 4-butyl ammonium fluoride trihydrate (2.374g, 7.53mmol)
Reason, and reaction is stirred at room temperature overnight.Then reaction mixture is poured into saturation NH4Cl and saturation NaHCO3It is water-soluble
In the mixture of liquid, and mixture is extracted with ethyl acetate three times.By combined organic matter through Na2SO4It dries, filters, and
It is concentrated in vacuum, and rough material is purified by silica gel chromatography, the elution of 0 to 20% ethyl acetate-heptane of use.Obtain title
Compound (6- cyclobutyl -2- methoxypyridine -3- base) methanol (through two steps, 0.102g, 35% yield).1H NMR
(501MHz, CDCl3) δ ppm 7.46 (dt, J=7.2,0.7Hz, 1H), 6.72 (d, J=7.3Hz, 1H), 4.64 (d, J=
6.4Hz, 2H), 4.05 (s, 3H), 3.57 (p, J=8.4Hz, 1H), 2.42-2.23 (m, 5H), 2.11-1.97 (m, 1H),
1.98-1.87 (m, 1H)；MS(ESI+)m/z 194.1(M+H)+。
Intermediate 13D
6- cyclobutyl -2- methoxyl group cigarette aldehyde
It will be in CH2Cl2In (3.5mL) (6- cyclobutyl -2- methoxypyridine -3- base) methanol (0.102g,
It 0.528mmol) is cooled to 0 DEG C, and crosses iodine alkane (0.269g, 0.633mmol) batch processing with Dai Si-Martin.After the completion of addition,
Reaction is removed from ice bath and allows to be stirred at room temperature 1 hour.Then by mixture 30mL methyl tertiary butyl ether(MTBE), 30mL
It is saturated Na2S2O3Aqueous solution and 30mL are saturated NaHCO3Aqueous solution dilution, and mixture is vigorously stirred 15 minutes.It will mix
It closes object to be transferred in separatory funnel, these mutually be separated, and organic layer is washed with brine, through Na2SO4It dries, filters, and
It is concentrated in a vacuum.Silica gel chromatography (being eluted with 0 to 20% ethyl acetate-heptane) provides title compound 6- cyclobutyl -2-
Methoxyl group cigarette aldehyde (0.081g, 80% yield).1H NMR (501MHz, CDCl3) δ ppm10.34 (s, 1H), 8.03 (d, J=
7.7Hz, 1H), 6.84 (dt, J=7.8,0.7Hz, 1H), 4.12 (s, 3H), 3.69-3.58 (m, 1H), 2.46-2.29 (m,
4H), 2.15-2.01 (m, 1H), 2.02-1.91 (m, 1H)；MS(ESI+)m/z 192.1(M+H)+。
Intermediate 14
6- tert-butyl -2- methoxv-pyridine -3- formaldehyde
Intermediate 14A
6- (tert-butyl) -2- methoxyl group nicotinic acid nitrile
Exist to the chloro- pyridine -3- formonitrile HCN of 6- tert-butyl -2- (CAS#4138-20-9,3.30g, 16.95mmol, 1.0 equivalent)
Added in agitating solution in methanol (25mL) in methyl alcohol 25 weight % solution of sodium methoxide (CAS#124-41-4,5.43mL,
23.73mmol, 1.4 equivalents).Reaction mixture is flowed back 2 hours.Addition saturation NH4Cl aqueous solution, and reaction mixture is used
Ethyl acetate is extracted twice.By combined organic layer through Na2SO4It dries, filters and is concentrated in a vacuum.Crude mixture is led to
Flashchromatography on silica gel (heptane/ethyl acetate 100/0 to 90/10) purifying is crossed, to provide title compound.1H NMR
(400MHz, chloroform-d) δ ppm 7.79 (d, J=7.9Hz, 1H), 6.98 (d, J=7.9Hz, 1H), 4.05 (s, 3H), 1.34
(s, 9H)；LC/MS(ESI+)m/z 191.3(M+H)+。
Intermediate 14B
6- tert-butyl -2- methoxv-pyridine -3- formic acid
Potassium hydroxide (CAS#1310-58-3,5.14g, 91.74mmol, 6.0 equivalent) is added to intermediate 14A
(2.91g, 15.29mmol, 1.0 equivalent) is in the agitating solution of methanol (80mL) and water (20mL).Reaction mixture is flowed back
It 72 hours and is concentrated in a vacuum.Rough material is acidified with 2N HCL aqueous solution (CAS#7607-01-0,58mL), and by gained
Material filtering is washed with water and is dried in a vacuum, to provide title compound.LC/MS(ESI+)m/z 210.2(M+H)+。
Intermediate 14C
Methyl 6- tert-butyl -2- methoxv-pyridine -3- formic acid esters
Sulfuric acid (CAS#7664-93-9,700 μ L, 13.06mmol, 0.85 equivalents) is added to the tertiary fourth of the 6- previously prepared
Base -2- methoxv-pyridine -3- formic acid (3.20g, 15.29mmol, 1.0 equivalent) is in the agitating solution in methanol (50mL).It will
Reaction mixture is refluxed overnight.It adds more sulfuric acid (CAS#7664-93-9,700 μ L, 13.06mmol, 0.85 equivalents) and incites somebody to action
Reaction mixture flows back 3 hours.Addition saturation NaHCO3Aqueous solution, and reaction mixture is extracted with ethyl acetate twice.It will
Combined organic layer is through Na2SO4It dries, filters and is concentrated in a vacuum.Crude mixture is passed through into flashchromatography on silica gel (two
Chloromethanes) purifying, to provide title compound.1H NMR (300MHz, chloroform-d) δ ppm 8.10 (d, J=7.9Hz, 1H),
6.94 (d, J=7.9Hz, 1H), 4.05 (s, 3H), 3.89 (s, 3H), 1.35 (s, 9H)；LC/MS(ESI+)m/z 224.6(M+
H)+。
Intermediate 14D
(6- tert-butyl -2- methoxyl group -3- pyridyl group) methanol
By lithium aluminium hydride reduction (the 1.0M solution in tetrahydrofuran, CAS#16853-85-3,34.47mL, 34.47mmol,
1.5 equivalents) be added to previously cooling (0 DEG C) methyl 6- tert-butyl -2- methoxv-pyridine -3- formic acid esters (5.13g,
22.98mmol, 1.0 equivalents) in the solution in tetrahydrofuran (70mL).Reaction mixture is stirred 1 hour and at 0 DEG C in room
Temperature lower stirring 1 hour.Using following post-processing to remove lithium salts.Reaction mixture is cooled to 0 DEG C, 1.3mL water is added dropwise, then
Add 1.3mL 15%NaOH aqueous solution and 3.25mL water.Mixture is stirred at room temperature 10 minutes then through diatomite mistake
Filter.By filtrate through Na2SO4It dries, filters and is concentrated in a vacuum, to provide title compound.LC/MS(ESI+)m/z 196.3
(M+H)+。
Intermediate 14E
6- tert-butyl -2- methoxv-pyridine -3- formaldehyde
At 0 DEG C, Dai Si-Martin is crossed into iodine alkane (CAS#87413-09-0,10.68g, 25.18mmol, 1.1 equivalent) addition
To (6- tert-butyl -2- methoxyl group -3- pyridyl group) methanol (4.47g, 22.89mmol, 1.0 equivalent) at methylene chloride (100mL)
In solution in.Reaction mixture is stirred 1 hour at 0 DEG C and allows to warm to room temperature.Addition saturation NaHCO3Aqueous solution is simultaneously
Organic layer is separated, through Na2SO4It dries, filters and is concentrated in a vacuum.Crude mixture is passed through into flashchromatography on silica gel (dichloro
Methane) purifying, to provide title compound.1H NMR (400MHz, chloroform-d) δ ppm 10.33 (s, 1H), 8.05 (d, J=
7.9Hz, 1H), 7.03 (d, J=7.9Hz, 1H), 4.07 (s, 3H), 1.37 (s, 9H)；LC/MS(ESI+)m/z 194.2(M+H)+。
Intermediate 15
2- methoxyl group -5- trimethylsilyl-pyridine -3- formaldehyde
Intermediate 15A
5- bromo- 3- [1,3] dioxolanes -2- base -2- methoxv-pyridine
By the p-methyl benzenesulfonic acid of ethylene glycol (CAS#107-21-1,0.51mL, 9.2mmol, 2.0 equivalent) and a spatula
(PTSA, CAS#104-15-4) is added to the bromo- 2- methoxyl group cigarette aldehyde of 5-, and (CAS#25016-01-7,1.0g, 4.6mmol, 1.0 work as
Amount) in the solution in toluene (20mL).Reaction mixture is heated to being refluxed overnight.Reaction mixture is cooled to room temperature simultaneously
It is diluted with ethyl acetate.By organic phase saturation NaHCO3Aqueous solution washing, in Na2SO4On dry, filter and dense in a vacuum
Contracting.Residue is purified by flashchromatography on silica gel (heptane/methylene chloride 90/10 to 20/80), to provide title compound
(795mg, 83%).LC/MS(ESI+)m/z 260.2(M+H)+。
Intermediate 15B
3- [1,3] dioxolanes -2- base -2- methoxyl group -5- trimethylsilyl-pyridine
At -78 DEG C, n-BuLi (2.5M in hexane, 1.25mL, 3.2mmol, 1.1 equivalents) is added to the bromo- 3- of 5-
[1,3] dioxolanes -2- base -2- methoxv-pyridine (746mg, 2.9mmol, 1.0 equivalent) is molten in tetrahydrofuran (10mL)
In liquid.By reaction mixture -78 DEG C stir 15 minutes, then be added dropwise trim,ethylchlorosilane (CAS#75-77-4,0.40mL,
3.2mmol, 1.1 equivalents).Gained mixture is allowed to warm to room temperature.After 1 hour, reaction mixture is quenched with water, in vacuum
Middle concentration is simultaneously extracted with dichloromethane.By combined organic phase in Na2SO4On dry, filter and be concentrated in a vacuum.It will slightly produce
Object can be used in next step without further purification.
Intermediate 15C
2- methoxyl group -5- trimethyl silyl-benzaldehyde
Intermediate 15B (1.0 equivalent) is dissolved in acetone (20mL).It adds the p-methyl benzenesulfonic acid (PTSA) of a spatula and incites somebody to action
Reaction mixture flows back 1 hour.Mixture is concentrated in a vacuum.Residue is passed through into flashchromatography on silica gel (heptane/dichloro
Methane 90/10 to 0/100) purifying, to provide title compound (through two steps, 292mg, 49%).1H NMR (400MHz,
Chloroform-d) δ ppm 10.40 (s, 1H), 8.45 (d, J=2.0Hz, 1H), 8.20 (d, J=2.0Hz, 1H), 4.08 (s, 3H),
0.30 (s, 9H)；LC/MS(ESI+)m/z 210.3(M+H)+。
Intermediate 16
2- methoxyl group -5- trimethylsilyl-benzaldehyde
Intermediate 16A
2- (the bromo- 2- methoxyl group-phenyl of 5-)-[1,3] dioxolanes
By the p-methyl benzenesulfonic acid of ethylene glycol (CAS#107-21-1,1.11mL, 20mmol, 2.0 equivalent) and a spatula
(PTSA, CAS#104-15-4) is added to 5- bromo- Benzaldehyde,2-methoxy (CAS#25016-01-7,2.15g, 10mmol, 1.0
Equivalent) in the solution in toluene (40mL).Reaction mixture is heated to being refluxed overnight.Reaction mixture is cooled to room temperature
And it is diluted with ethyl acetate.By organic phase saturation NaHCO3Aqueous solution washing, through Na2SO4It dries, filters and dense in a vacuum
Contracting.Residue is purified by flashchromatography on silica gel (heptane/methylene chloride 90/10 to 20/80), to provide title compound
(2.55g, 98%).1H NMR (400MHz, chloroform-d) δ ppm7.64 (d, J=2.6Hz, 1H), 7.42 (dd, J=8.9,
2.6Hz, 1H), 6.79 (d, J=8.9Hz, 1H), 6.11 (s, 1H), 4.18-3.99 (m, 4H), 3.85 (s, 3H).
Intermediate 16B
(3- [1,3] dioxolanes -2- base -4- methoxyl group-phenyl)-trimethyl-silane
At -78 DEG C, by n-BuLi (2.5M in hexane, 1.6mL, 4.0mmol, 1.1 equivalents), being added to 2-, (5- is bromo-
2- methoxyl group-phenyl)-solution of [1, the 3] dioxolanes (964mg, 3.7mmol, 1.0 equivalent) in tetrahydrofuran (10mL)
In.By reaction mixture -78 DEG C stir 15 minutes, and be added dropwise trim,ethylchlorosilane (CAS#75-77-4,0.51mL,
4.0mmol, 1.1 equivalents).Gained mixture is allowed to warm to room temperature.After l hours, reaction solution is quenched with water, in a vacuum
It is concentrated and is extracted with dichloromethane.By combined organic phase in Na2SO4On dry, filter and be concentrated in a vacuum.By crude product
It can be used in next step without further purification.LC/MS(ESI+)m/z 253.3(M+H+。
Intermediate 16C
2- methoxyl group -5- trimethylsilyl-benzaldehyde
Intermediate 16B (1.0 equivalent) is dissolved in acetone (20mL).It adds the p-methyl benzenesulfonic acid (PTSA) of a spatula and incites somebody to action
Reaction mixture flows back 1 hour.Mixture is concentrated in a vacuum.Residue is passed through into flashchromatography on silica gel (heptane/dichloro
Methane 90/10 to 50/50) purifying, to provide title compound (through two steps, 549mg, 71%).LC/MS(ESI+)m/z
209.3(M+H)+。
Intermediate 17
1- (3- formoxyl -4- methoxyl group-phenyl)-cyclobutane formonitrile HCN
Intermediate 17A
1- (3- [1,3] dioxolanes -2- base -4- methoxyl group-phenyl)-cyclobutane formonitrile HCN
By tris(dibenzylideneacetone) dipalladium (0) (Pd2(dba)3, CAS#51364-51-3,46mg, 0.05mmol, 0.05
Equivalent) and 2,2 '-bis- (diphenylphosphino) -1,1 '-dinaphthyl (BINAP, CAS#98327-87-8,62mg, 0.1mmol, 0.1
Equivalent) it is fitted into round-bottomed flask.Add anhydrous tetrahydro furan (2.0mL) and by reaction mixture N2Degassing.Mixture is existed
It stirs 20 minutes, and is added in bottle at room temperature, which contains 2- (the bromo- 2- methoxyl group-phenyl of 5-)-[1,3] dioxy penta
Ring (intermediate 16A, 259mg, 1.0mmol, 1.0 equivalent) and cyclobutane formonitrile HCN (CAS#4426-11-3,140 μ L, 1.5mmol,
1.5 equivalents) de gassed solution in tetrahydrofuran (1.0mL).Will be bis- (trimethyl silyl) amide lithium (1M is in tetrahydrofuran
In, CAS#4039-32-1,1.5mL, 1.5mmol, 1.5 equivalents) it is added slowly in reaction mixture.Bottle is sealed, and will
Reaction mixture stirs 3 hours at 80 DEG C.By mixture in saturation NH4It is distributed in Cl aqueous solution and ethyl acetate.By organic layer
Separation, in Na2SO4On dry, filter and be concentrated in a vacuum.Residue is passed through into flashchromatography on silica gel (methylene chloride/second
Acetoacetic ester 100/0 to 95/5) purifying, to provide title compound (134mg, 52%).1H NMR (400MHz, chloroform-d) δ ppm
(7.58 d, J=2.6Hz, 1H), 7.37 (dd, J=8.5,2.6Hz, 1H), 6.91 (d, J=8.5Hz, 1H), 6.12 (s, 1H),
4.21-3.98 (m, 4H), 3.87 (s, 3H), 2.86-2.72 (m, 2H), 2.67-2.51 (m, 2H), 2.47-2.31 (m, 1H),
2.11-1.97 (m, 1H)；LC/MS(ESI+)m/z 260.4(M+H)+。
Intermediate 17B
1- (3- formoxyl -4- methoxyl group-phenyl)-cyclobutane formonitrile HCN
By 1- (3- [1,3] dioxolanes -2- base -4- methoxyl group-phenyl)-cyclobutane formonitrile HCN (134mg, 0.52mmol,
1.0 equivalents) it is dissolved in acetone (15mL).It adds the p-methyl benzenesulfonic acid (PTSA) (CAS#104-15-4) of a spatula and mixes reaction
Object is closed to be stirred at room temperature 72 hours.Mixture is concentrated in a vacuum and by residue by flashchromatography on silica gel (heptane/
Methylene chloride 50/50 to 0/100) purifying, to provide title compound (51mg, 46%).LC/MS(ESI+)m/z 216.2(M+
H)+。
Intermediate 18
1- (3- formoxyl -4- methoxyl group-phenyl)-cyclopropanecarbonitrile
Intermediate 18A
1- (3- [1,3] dioxolanes -2- base -4- methoxyl group-phenyl)-cyclopropanecarbonitrile
By tris(dibenzylideneacetone) dipalladium (0) (Pd2(dba)3, CAS#51364-51-3,229mg, 0.25mmol, 0.05
Equivalent) and 2,2 '-bis- (diphenylphosphino) -1,1 '-dinaphthyl (BINAP, CAS#98327-87-8,311mg, 0.5mmol, 0.1
Equivalent) it is fitted into round-bottomed flask.Add anhydrous tetrahydro furan (5.0mL) and by reaction mixture N2Degassing.Mixture is existed
It stirs 20 minutes, and is added in bottle at room temperature, which contains 2- (the bromo- 2- methoxyl group-phenyl of 5-)-[1,3] dioxy penta
Ring (intermediate 16A, 1.3g, 5.0mmol, 1.0 equivalent) and cyclopropanecarbonitrile (CAS#5500-21-0,552 μ L, 7.5mmol,
1.5 equivalents) de gassed solution in cyclopentyl methyl ether (10mL).Will be bis- (trimethyl silyl) amide lithium (LiHMDS, 1M exist
In tetrahydrofuran, CAS#4039-32-1,7.5mL, 7.5mmol, 1.5 equivalents) it is added slowly in reaction mixture.By bottle
Sealing, and reaction mixture is stirred overnight at 80 DEG C.By mixture in saturation NH4It is distributed in Cl aqueous solution and ethyl acetate.
Organic layer is separated, is washed with brine, in Na2SO4On dry, filter and be concentrated in a vacuum.Residue is quick by silica gel
Chromatography (dichloromethane/ethyl acetate 100/0 to 95/5) purifying, to provide title compound (886mg, 72%).1H NMR
(400MHz, chloroform-d) δ ppm 7.44 (d, J=2.6Hz, 1H), 7.35 (dd, J=8.5,2.6Hz, 1H), 6.89 (d, J=
8.5Hz, 1H), 6.11 (s, 1H), 4.20-4.00 (m, 4H), 3.87 (s, 3H), 1.70-1.62 (m, 2H), 1.40-1.32 (m,
2H)；LC/MS(ESI+)m/z 246.3(M+H)+。
Intermediate 18B
1- (3- formoxyl -4- methoxyl group-phenyl)-cyclopropanecarbonitrile
By 1- (3- [1,3] dioxolanes -2- base -4- methoxyl group-phenyl)-cyclopropanecarbonitrile (245mg, 1.0mmol, 1.0
Equivalent) it is dissolved in acetone (20mL).It adds the p-methyl benzenesulfonic acid (PTSA) (CAS#104-15-4) of a spatula and mixes reaction
Object flows back 1.5 hours.Mixture is concentrated in a vacuum and residue is passed through into flashchromatography on silica gel (heptane/methylene chloride
50/50 to 0/100) it purifies, to provide title compound (157mg, 78%).LC/MS(ESI+)m/z 202.3(M+H)+。
Intermediate 19
2- tert-butyl -4- methoxy-pyrimidine -5- formaldehyde
At 0 DEG C, Dai Si-Martin is crossed into iodine alkane (CAS#87413-09-0,603mg, 1.46mmol, 1.5 equivalent) and is added to
[2- (tert-butyl) -4- methoxy pyrimidine -5- base] methanol (191mg, 0.976mmol, 1.0 equivalent) is in methylene chloride (7mL)
Solution in.Reaction mixture is stirred 1 hour at 0 DEG C and is filtered through diatomite.Residue is washed and incited somebody to action with methylene chloride
Filtrate is concentrated in a vacuum.Crude mixture is purified by flashchromatography on silica gel (heptane/ethyl acetate 90/10 to 85/15),
To provide title compound (117mg, 62%).LC/MS(ESI+)m/z 213.1(M+H2O+H)+。
Intermediate 20
6- cyclobutyl -3- methoxy-pyridazine -4- formaldehyde
Intermediate 20A
6- cyclobutyl -3- methoxy-pyridazine -4- methyl formate
Equipped in tetrahydrofuran (3mL) the chloro- 3- methoxyl group pyridazine -4- formic acid esters of methyl 6- (53mg,
0.26mmol, 1.0 equivalents) and Pd (PPh3)4(tetrakis triphenylphosphine palladium (0), CAS#14221-01-3,30mg, 0.026mmol,
0.1 equivalent) seal pipe in addition in tetrahydrofuran 0.5M cyclobutyl bromide solutions (CAS#38256-93-8,
2.1mL, 1.04mmol, 4.0 equivalent).By gained mixture N2It rinses, bottle is sealed and is heated to 70 DEG C until having reacted
At.NH is saturated by addition4Reaction mixture is quenched and is extracted with ethyl acetate by Cl aqueous solution.Organic phase is separated, salt is used
Water washing, in MgSO4On dry, filter and be concentrated in a vacuum.By residue by flashchromatography on silica gel (ethyl acetate/
Heptane 0/100 to 20/80) purifying, to provide title compound (30mg, 52%).LC/MS(ESI+)m/z 223.3(M+H)+。
Intermediate 20B
(6- cyclobutyl -3- methoxy-pyridazine -4- base)-methanol
By diisobutyl aluminium hydride (DIBAL-H, 1.0M solution in tetrahydrofuran, CAS#1191-15-7,1.25mL,
1.25mmol, 2.0 equivalents) it is added to the 6- cyclobutyl -3- methoxy-pyridazine -4- methyl formate of previously cooling (- 78 DEG C)
(137mg, 0.62mmol, 1.0 equivalent) is in the solution in toluene (5mL).Reaction mixture is warmed to 0 DEG C and stirs 15 points
Clock.Realization is fully completed.Reaction mixture is poured into ethyl acetate and saturation sodium potassium tartrate tetrahydrate tetrahydrate (Rochelle
Salt) aqueous solution mixture in.Mixture is vigorously stirred 30 minutes, until obtaining clear solution.Organic phase is separated, salt is used
Water washing, in MgSO4On dry, filter and be concentrated in a vacuum.Residue is passed through into flashchromatography on silica gel (heptane/acetic acid
Ethyl ester 80/20 to 50/50) purifying, to provide title compound (65mg, 54%).LC/MS(ESI+)m/z 195.3(M+H)+。
Intermediate 20C
6- cyclobutyl -3- methoxy-pyridazine -4- formaldehyde
At 0 DEG C, Dai Si-Martin is crossed into iodine alkane (CAS#87413-09-0,213mg, 0.50mmol, 1.5 equivalent) and is added to
(6- cyclobutyl -3- methoxy-pyridazine -4- base)-methanol (65mg, 0.33mmol, 1.0 equivalent) is in methylene chloride (5mL)
In solution.Reaction mixture is stirred at room temperature 1 hour and is filtered through diatomite.Residue is washed and incited somebody to action with methylene chloride
Filtrate is concentrated in a vacuum.Crude mixture is purified by flashchromatography on silica gel (heptane/ethyl acetate 100/0 to 80/20),
To provide title compound (56mg, 87%).LC/MS(ESI+)m/z 211.3(M+H2O+H)+。
Intermediate 21
(R) -2- methoxyl group -3- phenyl-propionic
At 0 DEG C, in N2Under, to NaH (60% suspension in the oil, 289mg, 7.2mmol, 2.5 equivalents) in tetrahydro
(R) -3-phenyl lactic acid is added in agitating solution in furans (15mL), and (CAS#7326-19-4,500mg, 3.0mmol, 1.0 work as
Amount).Gained mixture is warmed to room temperature and stirs 15 minutes, then add iodomethane (CAS#74-88-4,0.375mL,
6.02mmol, 2.0 equivalents).Reaction mixture is stirred at room temperature 16 hours, the aqueous HCl of 1N is then added and mixes gained
Object is closed to be concentrated in a vacuum.HCl (1N is aqueous) is added in residue and extracts mixture with diethyl ether.By having for merging
Machine layer is washed with brine, through MgSO4It dries, filters and is concentrated in a vacuum.Thick residue is passed through into flashchromatography on silica gel (second
Acetoacetic ester/heptane/acetic acid 20/80/1) purifying, to provide title compound (223mg, 41%).1H NMR (400MHz, chloroform-
D) δ ppm 7.37-7.23 (m, 5H), 4.05 (dd, J=7.9,4.3Hz, 1H), 3.41 (s, 3H), 3.17 (dd, J=15.9,
4.3Hz, 1H), 3.04 (dd, J=15.9,7.9Hz, 1H)；LC/MS(ESI-)m/z 179.1(M-H)-。
Intermediate 22
(3,4- difluorophenyl)-methoxyl group-acetic acid
Under argon gas, at 0 DEG C, to 3,4- difluorobenzaldehyde, (CAS#34036-07-2,522 μ L, 5.0mmol, 1.0 work as
Amount) and bromofom (CAS#75-25-2,555 μ L, 6.35mmol, 1.27 equivalents) KOH is added dropwise in the solution in dioxanes (5mL)
The solution of (281mg, 5.0mmol, 1.0 equivalent) in methanol (10mL).Gained mixture is stirred at room temperature overnight, is used
The dilution of 10mL water, and Evaporation of methanol.By addition HCL aqueous solution by water layer acidification up to pH=3-4, and it is extracted with ethyl acetate
Several times.Combined organic phase is washed with brine, through MgSO4It dries, filters and is concentrated in a vacuum.Thick residue is passed through into silicon
Glue flash chromatography (ethyl acetate/heptane/acetic acid 30/70/2) purifying, to provide title compound (392mg, 39%).LC/
MS(ESI-)m/z 201.2(M-H)-。
Intermediate 23
(the chloro- phenyl of 3-)-methoxyl group-acetic acid
Under argon gas, at 0 DEG C, to 3- chlorobenzaldehyde (CAS#587-04-2,569 μ L, 5.0mmol, 1.0 equivalents) and bromine
Imitative (CAS#75-25-2,525 μ L, 6.0mmol, 1.2 equivalents) be added dropwise in the solution in methanol (5mL) KOH (1.4g,
25.0mmol, 5.0 equivalents) solution in methanol (10mL).Gained mixture is stirred at room temperature overnight, 10mL is then used
Water is diluted and is extracted with dichloromethane.Organic layer is separated.By addition HCL aqueous solution by water layer acidification up to pH=3-4, and
It is extracted with dichloromethane several times.Combined organic phase is washed with brine, through MgSO4It dries, filters and is concentrated in a vacuum.It will
Thick residue is purified by flashchromatography on silica gel (ethyl acetate/heptane/acetic acid 20/80/1), to provide title compound
(636mg, 63%).1H NMR (400MHz, chloroform-d) δ ppm 7.50-7.44 (m, 1H), 7.38-7.30 (m, 3H), 4.77
(s, 1H), 3.45 (s, 3H)；LC/MS(ESI-)m/z 199.1(M-H)-。
Intermediate 24
2- methoxyl group -3,3- Dimethyl-butyric acid
Intermediate 24A
2- hydroxyl -3,3- Dimethyl-butyric acid benzyl ester
Benzyl bromide (CAS#100-39-0,0.65mL, 5.5mmol, 1.5 equivalent) is added to 2- hydroxyl -3,3- dimethyl
Butyric acid (472mg, 3.6mmol, 1.0 equivalent) and triethylamine (0.76mL, 5.5mmol, 1.5 equivalent) are in n,N-Dimethylformamide
In solution in (5mL).Reaction mixture is stirred at room temperature overnight, is then distributed between water and ethyl acetate.To have
Machine layer is washed with brine, in Na2SO4On dry, filter and be concentrated in a vacuum.Residue is passed through into flashchromatography on silica gel (heptan
Alkane/methylene chloride 100/0 to 0/100) purifying, to provide title compound (595mg, 75%).1H NMR (400MHz, chloroform-
D) δ ppm 7.41-7.34 (m, 5H), 5.27-5.19 (m, 2H), 3.86 (d, J=7.7Hz, 1H), 2.78 (d, J=7.7Hz,
1H), 0.96 (s, 9H)；LC/MS(ESI+)m/z 245.3(M+Na)+。
Intermediate 24B
2- methoxyl group -3,3- Dimethyl-butyric acid benzyl ester
At 0 DEG C, to 2- hydroxyl -3,3- Dimethyl-butyric acid benzyl ester (430mg, 1.93mmol, 1.0 equivalent) in N, N- bis-
NaH (60% suspension in the oil, 93mg, 2.32mmol, 1.2 equivalents) are added in solution in methylformamide (5mL).It stirs
After mixing 15 minutes, add iodomethane (CAS#74-88-4,0.36mL, 5.8mmol, 3.0 equivalent).By reaction mixture in room temperature
Lower stirring 48 hours is saturated NH by addition4The quenching of Cl aqueous solution, and be extracted with ethyl acetate.Organic layer is separated, salt water is used
Washing, through Na2SO4It dries, filters and is concentrated in a vacuum.Residue is passed through into flashchromatography on silica gel (heptane/methylene chloride
90/10 to 20/80) it purifies, to provide title compound (275mg, 60%).1H NMR (400MHz, chloroform-d) δ ppm
7.45-7.30 (m, 5H), 5.26-5.16 (m, 2H), 3.45 (s, 1H), 3.36-3.31 (m, 3H), 1.01-0.92 (m, 9H).
Intermediate 24C
2- methoxyl group -3,3- Dimethyl-butyric acid
In N2Under, to 2- methoxyl group -3,3- Dimethyl-butyric acid benzyl ester (375mg, 1.59mmol, 1.0 equivalent) in acetic acid second
Palladium charcoal 5% (38mg, 10%w/w) and ammonium formate (CAS# are added in solution in the mixture of ester (5mL) and methanol (5mL)
540-69-2,1.22g, 15.9mmol, 10 equivalent).Reaction mixture is heated to reflux and continues 18 hours.Then reaction is mixed
Object is closed to be concentrated and dilute in ethyl acetate in a vacuum.Suspension is filtered through diatomite.Filtrate is washed with 1MHCl aqueous solution
It washs, in Na2SO4On dry, filter and be concentrated in a vacuum, to provide title compound (150mg, 65%), by it without into one
Step purifying is directly used in next step.1H NMR (400MHz, chloroform-d) δ ppm 3.44 (s, 3H), 3.42 (s, 1H), 1.02
(s, 9H).
Intermediate 25
Racemic-(S) -2- ((R)-tetrahydro -2H- pyrans -2- base) propionic acid
Intermediate 25A
(ttetrahydro-pyran -2- base)-benzyl acetate
Benzyl bromide (CAS#100-39-0,1.07mL, 9.0mmol, 1.3 equivalent) is added to 2- oxinane -2- base second
Sour (1.0g, 6.93mmol, 1.0 equivalent) and triethylamine (1.54mL, 11.1mmol, 1.6 equivalent) are in tetrahydrofuran (20mL)
Solution in.Reaction mixture is stirred 2 hours at 50 DEG C, with saturation NH4Cl aqueous solution dilutes and is extracted with ethyl acetate two
It is secondary.By combined organic layer through Na2SO4It dries, filters and is concentrated in a vacuum.Residue is passed through into flashchromatography on silica gel
(heptane/ethyl acetate 100/0 to 80/20) purifying, to provide title compound (330mg, 20%).1H NMR (400MHz, chlorine
Imitative-d) δ ppm 7.43-7.29 (m, 5H), 5.17 (d, J=12.1Hz, 1H), 5.12 (d, J=12.1Hz, 1H), 4.02-3.93
(m, 1H), 3.83-3.72 (m, 1H), 3.52-3.40- (m, 1H), 2.58 (dd, J=15.0,8.5Hz, 1H), 2.45 (dd, J=
15.0,4.8Hz, 1H), 1.91-1.76 (m, 1H), 1.70-1.43 (m, 4H), 1.41-1.23 (m, 1H)；LC/MS(ESI+)m/z
235.2(M+H)+。
Intermediate 25B
Racemic-(S)-(R) -2- (ttetrahydro-pyran -2- base)-benzyl propionate
At -78 DEG C, under argon gas, to (ttetrahydro-pyran -2- base), (322mg, 1.37mmol, 1.0 work as-benzyl acetate
Amount) add 1,3- dimethyl -3,4 in the solution in tetrahydrofuran (15mL), -2 (1H)-pyrimidone of 5,6- tetrahydro (DMPU,
CAS#7226-23-5,4.14mL, 34.3mmol, 25 equivalent).2.0M is introduced dropwise in tetrahydrofuran/heptane/ethylo benzene
Lithium diisopropylamide solution (1.03mL, 2.06mmol, 1.5 equivalent).After -78 DEG C are stirred 1 hour, iodomethane is added
(CAS#74-88-4,428 μ L, 6.87mmol, 5.0 equivalents).Gained mixture was slowly warmed to room temperature through 2 hours, and in room
It is stirred overnight under temperature.Then pass through addition saturation NH4Reaction mixture is quenched and is extracted with ethyl acetate by Cl aqueous solution.To have
Machine mutually separates, and is washed with brine, in Na2SO4On dry, filter and be concentrated in a vacuum.Residue is passed through into flash chromatography on silica gel
Method (heptane/ethyl acetate 100/0 to 80/20) purifying with separate diastereoisomer and provide title compound (34mg,
10%, the second diastereoisomer of elution).1H NMR (400MHz, chloroform-d) δ ppm 7.41-7.28 (m, 5H), 5.22
(d, J=12.5Hz, 1H), 5.13 (d, J=12.5Hz, 1H), 4.02-3.88 (m, 1H), 3.55-3.35 (m, 2H), 2.66-
2.52 (m, 1H), 1.93-1.76 (m, 1H), 1.73-1.38 (m, 4H), 1.33-1.20 (m, 1H), 1.13 (d, J=7.2Hz,
3H)。
Intermediate 25C
Racemic-(S)-(R) -2- (ttetrahydro-pyran -2- base)-propionic acid
In N2Under, to racemic-(S)-(R) -2- (ttetrahydro-pyran -2- base)-benzyl propionate (34mg, 0.14mmol, 1.0
Equivalent) addition palladium charcoal 10% (14mg, 0.0137mmol, 0.1 equivalent) in the solution in methanol (5mL).Then solution is taken off
Gas uses H2It rinses and is stirred at room temperature 2 hours.Then reaction mixture is filtered over celite, in a vacuum by filtrate
It is directly used in next step by concentration without further purification with providing title compound (22mg, quantitative).
Intermediate 26
Racemic-(S) -2- ((S)-tetrahydro -2H- pyrans -2- base) propionic acid
Intermediate 26A
Racemic-(S)-(S) -2- (ttetrahydro-pyran -2- base)-benzyl propionate
Obtaining the title compound in the reaction described in intermediate 25B, (39mg, 11%, the first of elution is diastereomeric
Isomers).1H NMR (400MHz, chloroform-d) δ ppm 7.42-7.28 (m, 5H), 5.19 (d, J=12.5Hz, 1H), 5.11
(d, J=12.5Hz, 1H), 4.04-3.94 (m, 1H), 3.57-3.47 (m, 1H), 3.46-3.35 (m, 1H), 2.56 (quin, J
=6.9Hz, 1H), 1.89-1.76 (m, 1H), 1.59-1.29 (m, 5H), 1.23 (d, J=6.9Hz, 3H).
Intermediate 26B
Racemic-(S) -2- ((S)-tetrahydro -2H- pyrans -2- base) propionic acid
In N2Under, to racemic-(S)-(S) -2- (ttetrahydro-pyran -2- base)-benzyl propionate (39mg, 0.16mmol, 1.0
Equivalent) addition palladium charcoal 10% (17mg, 0.016mmol, 0.1 equivalent) in the solution in methanol (5mL).Then solution is taken off
Gas uses H2It rinses and is stirred at room temperature 2 hours.Then reaction mixture is filtered over celite, in a vacuum by filtrate
It is directly used in next step by concentration without further purification with providing title compound (24mg, 97%).
Core
Core 1
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
Core 1A
(E)-tert-butyl 2- (benzylideneamino) acetic acid esters
By glycine tert-butyl hydrochloride (6.95g, 41.5mmol) and magnesium sulfate (5.67g, 47.1mmol) in CH2Cl2
Mixture in (60mL) is handled with triethylamine (5.78mL, 41.5mmol), is stirred 15 minutes, with benzaldehyde (3.82mL,
It 37.7mmol) handles and is stirred at room temperature overnight.Mixture is filtered to remove solid and by solid CH2Cl2Washing.It will
Combined filtrate water (20mL) washing.By these layers of separation and by water layer CH2Cl2(about 15mL) extraction.By merging
CH2Cl2Dry (the MgSO of layer4), it filters and is concentrated (room-temperature water bath), to provide title compound.1H NMR (400MHz, CDCl3)δ
Ppm 8.27 (s, 1H), 7.80-7.76 (m, 2H), 7.47-7.37 (m, 3H), 4.31 (s, 2H), 1.50 (s, 9H)；MS(ESI+)
m/z 220(M+H)+。
Core 1B
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
In N2Under, by (E)-tert-butyl 2- (benzylideneamino) acetic acid esters (3.23g, 14.75mmol) in tetrahydrofuran
Solution in (30mL) is cooled to -78 DEG C, 1.5M lithium bromide (14.75mL, the 22.12mmol) processing in tetrahydrofuran,
With solution processing of (E) -3,3- dimethyl -1- nitro but-1-ene (2g, 15.49mmol) in tetrahydrofuran (20mL), with 1,
11 carbon -7- alkene (3.11mL, 20.65mmol) of 8- diazabicylo [5.4.0] is handled dropwise, and is stirred overnight, and allows to mix
Object slowly warms to room temperature.Mixture methyl tertiary butyl ether(MTBE) (about 150mL) is diluted and uses 10%KH2PO4Aqueous solution (30mL)
Washing.Solid by filtration present in mixture is separated and abandoned.Methyl tert-butyl ether layers are separated, with more 10%
KH2PO4Aqueous solution washing, is washed with brine, dry (MgSO4), it filters and is concentrated.Residue is handled with heptane.Gained is consolidated
Body is collected by filtration.Solid methyl tertiary butyl ether(MTBE) (about 30mL) and heptane (about 30mL) are handled and heated to dissolve big portion
Divide solid and evaporates methyl tertiary butyl ether(MTBE).It is allowed to stand at room temperature for 30 minutes n-heptane solution.Material is collected by filtration, heptan is used
Alkane washing, and (70 DEG C) are heated under vacuum drying 30 minutes, to provide desired product (1.09g).Both the above is filtered
Liquid merges, and concentration is dissolved in CH2Cl2In, it is handled and is concentrated to dryness with silica gel (8g).Silica gel suspension is subjected to silica gel chromatograph,
The gradient elution of 10% to 30% ethyl acetate in heptane, to provide other desired product (0.67g).It wishes
The total yield of the product of prestige is 1.76g.1H NMR (400MHz, DMSO-d6) δ ppm 7.42-7.37 (m, 2H), 7.35-7.24
(m, 3H), 5.43 (dd, J=6.4,2.9Hz, 1H), 4.46 (dd, J=10.5,6.5Hz, 1H), 3.66-3.61 (m, 1H),
3.38 (t, J=9.8Hz, 1H), 2.81 (dd, J=7.4,2.9Hz, 1H), 1.48 (s, 9H), 0.98 (s, 9H)；MS(ESI+)m/
z 349(M+H)+。
Core 2
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
Core 2A
(E)-ethyl 2- (benzylideneamino) acetic acid esters
To glycine ethyl ester hydrochloride (7.23g, 51.8mmol) and magnesium sulfate (7.09g, 58.9mmol) in methylene chloride
Triethylamine (7.22mL, 51.8mmol) is added in mixture in (80mL).Mixture is stirred at ambient temperature 20 minutes,
And benzaldehyde (4.79mL, 47.1mmol) is added dropwise.The mixture was stirred overnight.Reaction mixture is filtered, and by solid with two
Chloromethanes (20mL x 2) washing.Combined organic layer is washed with brine, through MgSO4It is dried, filtered and concentrated, to provide
(E)-ethyl 2- (benzylideneamino) acetic acid esters 8.2g (91% yield).1H NMR (400MHz, CDCl3) δ ppm 8.30 (s,
1H), 7.83-7.71 (m, 2H), 7.48-7.37 (m, 2H), 4.40 (d, J=J=1.4Hz, 2H), 4.24 (q, J=J=
7.1Hz, 2H), 1.30 (t, J=J=7.1Hz, 3H)；MS(ESI+)m/z 292.1(M+H)+。
Core 2B
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
To core 2A (1.0g, 5.23mmol) and (E) -3,3- dimethyl -1- nitro but-1-ene (0.810g, 6.28mmol)
In solution in ice bath in cooling toluene (30mL) addition acetyl group (oxo) silver-colored (1.309g, 7.84mmol) andPoint
Son sieve.Triethylamine (1.458mL, 10.46mmol) is added slowly in the reaction mixture being sufficiently stirred.10 are stirred at 0 DEG C
After minute, so that reaction mixture is warmed to environment temperature and be stirred for 4 hours.Saturated aqueous ammonium chloride is added, by sediment
It filters out and extracts residue with ether.By combined organic fraction through MgSO4It dries, filters, is concentrated, and by 40g silica gel
Chromatography is carried out on column and is purified, ethyl acetate (0-40% gradient) elution in heptane, to provide title compound
(1.6g, 95% yield).1H NMR (400MHz, CDCl3) δ ppm 7.39-7.26 (m, 5H), 5.12 (dd, J=J=6.0,
2.5Hz, 1H), 4.44 (d, J=J=5.7Hz, 1H), 4.31 (q, J=J=7.2Hz, 2H), 3.81 (d, J=J=7.1Hz,
1H), 3.30 (s, 1H), 2.95 (dd, J=J=7.1,2.5Hz, 1H), 1.34 (t, J=J=7.2Hz, 3H), 1.06 (s, 9H)；
MS(ESI+)m/z 321(M+H)+。
Core 3
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -2-
Formic acid esters
Core 3A
(E)-ethyl 2- ((2- benzylidene) amino) acetic acid esters
Exist to ethyl 2- amion acetic acid ester hydrochloride (10.76g, 77.12mmol) and magnesium sulfate (10.61g, 88.2mmol)
Triethylamine (11.2mL, 80.8mmol) is added in mixture in methylene chloride (100mL).Mixture is stirred at room temperature 20
Simultaneously Benzaldehyde,2-methoxy (10.0g, 73.45mmol) is added dropwise in minute.Gained mixture is stirred at room temperature overnight.By solid
It filters out and is washed with methylene chloride (300mL).Combined filtrate water (150mL) and salt water (150mL) are washed, through magnesium sulfate
Be dried, filtered and concentrated, with provide title compound (E)-ethyl 2- ((2- benzylidene) amino) acetic acid esters (16g,
50.60mmol, 68.9% yield).1H NMR (400MHz, CDCl3) δ ppm 8.73 (s, 1H), 8.01 (d, J=8.0Hz, 1H),
7.37-7.44 (m, 1H), 6.89-7.00 (m, 2H), 4.40 (s, 2H), 4.20-4.26 (m, 2H), 3.85 (s, 3H), 1.28-
1.31 (m, 3H).
Core 3B
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -2-
Formic acid esters
At -78 DEG C, to (E)-ethyl 2- ((2- benzylidene) amino) acetic acid esters (26.72g, 120.94mmol)
It is added dropwise in tetrahydrofuran (20mL) in the solution in tetrahydrofuran (220mL) with lithium bromide (13.90g, 131.02mmol)
(E) -3,3- dimethyl -1- nitro but-1-ene (13.0g, 110.78mmol) and DBU (1,8- diazabicylo [5.4.0] ten
One carbon -7- alkene, 22.6mL, 151.18mmol).Mixture is stirred 2.5 hours at -78 DEG C, and uses saturated aqueous ammonium chloride
(100mL) quenching, is extracted with ethyl acetate (2x150mL), is washed, be dried over sodium sulfate with salt water (2x150mL), is filtered and dense
Contracting.Residue is ground with petroleum ether (100mL).Solid by filtration is collected and is dried in a vacuum, it is titled to provide
Close beyond the region of objective existence racemization-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -2- formic acid
Ester (10.3g, 29.43mmol, 28.3% yield).1H NMR (400MHz, CDCl3) δ ppm 7.22-7.28 (m, 2H), 6.86-
6.95 (m, 2H), 5.33-5.35 (m, 1H), 4.56 (s, 1H), 4.30-4.32 (m, 2H), 3.89 (s, 3H), 3.77 (d, J=
8.0Hz, 1H), 3.36 (d, J=7.2Hz, 1H), 2.88-2.90 (m, 1H), 1.34 (d, J=7.2Hz, 3H), 1.05 (s, 9H)；
LC-MS(ESI+)m/z 351(M+H)+。
Core 4
Racemic-(2R, 3S, 4R, 5R)-benzyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
Core 4A
(E)-benzyl 2- (benzylideneamino) acetic acid esters
To benzyl 2- amion acetic acid ester hydrochloride (CAS#2462-31-9) (5g, 21.00mmol) and magnesium sulfate (3.16g,
26.2mmol) triethylamine (3.22mL, 23.10mmol) is added in the mixture in methylene chloride (80mL).Mixture is stirred
It mixes 20 minutes, is added dropwise benzaldehyde (2.348mL, 23.10mmol), and mixture is stirred overnight at ambient temperature.It will mixing
Object filters and washs solid with methylene chloride.Combined organic layer is washed with brine, through MgSO4It is dried, filtered and concentrated,
To provide (E)-benzyl 2- (benzylideneamino) acetic acid esters (5.3g, 100% yield).1H NMR (400MHz, CDCl3)δppm
8.28 (s, 1H), 7.84-7.70 (m, 2H), 7.48-7.26 (m, 8H), 5.21 (s, 2H), 4.44 (d, J=J=1.3Hz, 2H)；
MS(ESI+)m/z 254(M+H)+。
Core 4B
Racemic-(2R, 3S, 4R, 5R)-benzyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
Use core 4A as starting material, with method synthesising title compound identical with core 1B.LC/MS(ESI+)m/z
378.37(M+H)+。
Core 5
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitre
Base pyrrolidines -2- formic acid esters
Core 5A
2- (dimethylamino) cigarette aldehyde
By dimethylamine (aqueous solution, 10mL, 79mmol) use 10mL methanol dilution, and disposably add 2- chlorine cigarette aldehyde (5.0g,
35.3mmol).Reaction mixture is heated to 55 DEG C and continues 24 hours, and adds 10mL dimethylamine solution again.After 24 hours
Afterwards, starting material has been consumed.Reaction mixture is cooled to room temperature, diluted with the aqueous ammonium chloride of saturation and is extracted with methylene chloride
It takes.Combined extract is concentrated, and via purified by flash chromatography, 0-20% ethyl acetate/heptane is used on 80g silicagel column
Elution 20 minutes.Obtain desired product (3.9988g, 75%).1H NMR (501MHz, CDCl3) δ ppm 9.96 (s, 1H),
8.31 (dd, J=J=4.6,2.0Hz, 1H), 7.94 (dd, J=J=7.6,2.0Hz, 1H), 6.77 (dd, J=J=7.6,
4.6Hz, 1H), 3.13 (s, 6H)；LC-MS(ESI+)m/z 151.1(M+H)+。
Core 5B
(E)-ethyl 2- (((2- (dimethylamino) pyridin-3-yl) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (3.72g, 26.6mmol) and magnesium sulfate (6.41g, 53.3mmol) are suspended
In methylene chloride (44.4mL).By suspension 2- (dimethylamino) cigarette aldehyde (4g, 26.6mmol) and triethylamine
(3.71mL, 26.6mmol) processing, and mixture is stirred at room temperature 16 hours.Solid material is removed via filtering, and
Filtrate water is washed, is dried over sodium sulfate, filters and is concentrated to provide thick imines (5.76g, 92%), by it without other
Purifying uses.1H NMR (400MHz, CDCl3) δ ppm 8.42-8.37 (m, 1H), 8.26 (dd, J=4.8,2.0Hz, 1H),
8.06 (dd, J=7.6,1.9Hz, 1H), 6.84 (ddd, J=7.6,4.8,0.6Hz, 1H), 4.40 (d, J=1.3Hz, 2H),
4.23 (q, J=7.1Hz, 2H), 2.97 (s, 6H), 1.29 (t, J=7.1Hz, 3H).
Core 5C
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitre
Base pyrrolidines -2- formic acid esters
By (E)-ethyl 2- (((2- (dimethylamino) pyridin-3-yl) methylene) amino) acetic acid esters (3.31g,
It 14.07mmol) is dissolved in 60mL tetrahydrofuran.Acquired solution is cooled to -78 DEG C in acetone-dry ice bath, is added later
(E) -3,3- dimethyl -1- nitro but-1-ene (1.58g, 12.23mmol) and lithium bromide (10.60mL, 15.90mmol).Via
2,3,4,6,7,8,9,10- octahydro pyrimido [1,2-a] azepines are added dropwise in syringe(2.104mL, 14.07mmol), and by institute
The yellow mixture obtained stirs 2 hours at -78 DEG C, is then warmed to environment temperature, then with the aqueous ammonium chloride (30mL) of saturation
Quenching.Be concentrated by the mixture methyl tertiary butyl ether(MTBE) of 3x15mL extraction and in a vacuum to provide thick residue, by its via
Purified by flash chromatography, with 0: 100 to 30: 70 ethyl acetate on 80g silicagel column: heptane elutes 20 minutes, to provide 2.20g
Title compound.1H NMR (501MHz, CDCl3) δ ppm 8.30 (dd, J=4.8,1.8Hz, 1H), 7.62 (ddd, J=
7.6,1.8,0.8Hz, 1H), 6.99 (dd, J=7.7,4.8Hz, 1H), 5.48 (dd, J=5.7,2.4Hz, 1H), 4.62 (dd, J
=12.3,5.7Hz, 1H), 4.31 (qd, J=7.2,1.6Hz, 2H), 3.80 (dd, J=9.7,7.1Hz, 1H), 3.18 (t, J=
11.2Hz, 1H), 2.94-2.90 (m, 1H), 2.79 (s, 6H), 1.34 (t, J=7.1Hz, 3H), 1.07 (s, 10H)；MS(ESI
+)m/z 365.2(M+H)+。
Core 6
(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.583g, 0.774mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.127g, 0.252mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 0.5 hour
In (60mL).Gained mixture is stirred 1 hour (continuing nitrogen jet) at 25 DEG C, and adds (E)-tert-butyl 2- (benzal
Amino) solution of the acetic acid esters (core 1A, 16.98g, 77mmol) in 4mL tetrahydrofuran, and acquired solution is cold in ice-water bath
But to 5 DEG C of <.It is added dropwise 2- methyl propyl- 2- potassium alcoholate (0.134g, 1.20mmol), then through 10 minutes addition (E) -3,3- diformazans
Base -1- nitro but-1-ene (5g, 38.7mmol) keeps temperature to be lower than 7 DEG C.Reaction mixture is stirred 45 minutes at 0 DEG C.
Reaction 150mL is saturated aqueous ammonium chloride to quench, 20mL ether is added and mixture is warmed to 15 DEG C.Ether layer is separated,
It is washed with the aqueous ammonium chloride (2x150mL) of saturation and salt water (200mL), through Na2SO4(45g) is dried, filtered, and is then concentrated, with
(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters is provided.At 15 DEG C, by material
It is diluted 10 hours with normal heptane (150mL), filters simultaneously dry cake, then with offer (2S, 3R, 4S, 5S)-tert-butyl 3- (uncle
Butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (9g, 25.8mmol, 71.1% yield).1H NMR (400MHz,
CDCl3) δ ppm 7.36-7.30 (m, 5H), 5.13 (dd, J=2.2,5.7Hz, 1H), 4.44 (d, J=5.3Hz, 1H), 3.72
(d, J=6.6Hz, 1H), 3.43-3.23 (m, 1H), 2.88 (dd, J=2.2,7.1Hz, 1H), 1.55 (s, 9H), 1.07 (s,
9H)。
Core 7
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
Core 7A
(E)-ethyl 2- (benzylideneamino) acetic acid esters
At ambient temperature, by ethyl 2- amion acetic acid ester hydrochloride (30g, 215mmol) and magnesium sulfate (51.7g,
430mmol) the stirring in methylene chloride (358mL), and add triethylamine (30.0mL, 215mmol).Gained suspension is stirred
5 minutes, and benzaldehyde (21.78mL, 215mmol) is added dropwise via syringe.Then mixture is stirred 16 at ambient temperature
Hour.Solid material is removed by sinter funnel via filtering, and filter cake is washed with 20mL methylene chloride.Filtrate is used
The water washing of 2x20mL, is dried over sodium sulfate, and filters and is concentrated, to provide title compound.1H NMR (501MHz, CDCl3)δ
Ppm 8.30 (d.J=1.4Hz, 1H), 7.82-7.74 (m, 2H), 7.50-7.36 (m, 3H), 4.40 (d, J=1.3Hz, 2H),
4.24 (q, J=7.2Hz, 2H), 1.30 (t, J=7.2Hz, 3H).
Core 7B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (2.98g, 3.96mmol) and copper trifluoromethanesulfcomposite (I)
Dimer benzene complex (0.859g, 1.707mmol；90% technical grade, Aldrich) it is dissolved in and being sprayed 2 hours with nitrogen stream
Tetrahydrofuran (697mL) in.Gained mixture is stirred 90 minutes at ambient temperature, flask is cooled to lower than 5 at this time
DEG C internal temperature.(E)-ethyl 2- (benzylideneamino) acetic acid esters (73.3g, 383mmol) is disposably added via syringe.
It is added dropwise 2- methyl propyl- 2- potassium alcoholate (2.73mL, 2.73mmol, the 1M solution in tetrahydrofuran), then via syringe through 25
Minute adds pure (E) -3,3- dimethyl -1- nitro but-1-ene (45g, 348mmol), is kept for 10 DEG C of internal temperature <.Addition
After the completion, reactant is stirred for 5 minutes at the same temperature, LC-MS shows that starting nitro alkene converts completely at this time.It will be anti-
It answers mixture 300mL methyl tertiary butyl ether(MTBE) to dilute, and stirs 15 together with the aqueous ammonium chloride of 300mL saturation at ambient temperature
Minute.These layers are separated, organic layer is saturated aqueous ammonium chloride and salt water washing and are dried over sodium sulfate.It, will after filtering
Organic extract is concentrated in a vacuum, and to provide thick residue (140g), it is precipitated from 800mL heptane.By obtained solid
It is removed, is dried with the cold heptane wash of 200mL, and in vacuum drying oven to constant weight, to provide via filtering using sinter funnel
72.5g title compound.1H NMR (400MHz, CDCl3) δ ppm7.37-7.18 (m, 5H), 5.13 (dd, J=6.0,2.5Hz,
1H), 4.45 (dd, J=12.4,6.0Hz, 1H), 4.32 (qd, J=7.2,1.2Hz, 2H), 3.82 (dd, J=9.7,7.1Hz,
1H), 3.30 (dd, J=12.3,9.8Hz, 1H), 2.96 (dd, J=7.2,2.5Hz, 1H), 1.35 (t, J=7.1Hz, 3H),
1.06 (s, 9H)；MS(ESI+)m/z 321.1(M+H)+；[α]24.8=+16.1 ° (c=1, methanol).
Core 8
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 8A
(E)-ethyl 2- ((2- isopropyl benzal) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (5.02g, 36.0mmol) and magnesium sulfate (5.20g, 43.2mmol) are suspended
It is handled in methylene chloride (45mL), and with triethylamine (9.9mL, 71.0mmol).Heterogeneous white mixture is stirred 20 minutes,
And handled dropwise with 2- propylbenzyl aldehyde (5g, 33.7mmol), form yellow heterogeneous mixture.By reaction mixture in room temperature
Lower stirring 3 days.Mixture is filtered into (sintered glass funnel), and with a large amount of CH2Cl2Wash filter bed.Filtrate water is washed twice
And it is washed with brine once, through Na2SO4It dries, filters and is concentrated in a vacuum, to provide title compound, 7.066g (90%
Yield).1H NMR (400MHz, CDCl3) δ ppm8.73 (m, 1H), 7.94 (dd, J=J=7.9,1.5Hz, 1H), 7.42 (m,
1H), 7.35 (dd, J=J=7.9,1.4Hz, 1H), 7.24 (m, 1H), 4.44 (d, J=J=1.4Hz, 2H), 4.26 (q, J=J
=7.1Hz, 2H), 3.53 (hept, J=J=6.8Hz, 1H), 1.34-1.29 (m, 9H)；MS(ESI+)m/z 234.1(M+H)+。
Core 8B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Tetrahydrofuran (30mL) is used nitrogen jet 75 minutes, and adds copper trifluoromethanesulfcomposite (I) dimer benzene complex
(0.033g, 0.065mmol) and (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- bis-
Hydrogen oxazole -2- base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.098g, 0.129mmol).Mixing
It is orange that object becomes medium palm fibre-, and is stirred at room temperature 1 hour.It is then cooled to 5 DEG C of <, and with (E)-ethyl 2- ((2-
Isopropyl benzal) amino) solution of the acetic acid esters (4.15g, 17.80mmol) in 8mL tetrahydrofuran handles dropwise, then drips
Adding 2- methyl propyl- 2- potassium alcoholate, (1M is in tetrahydrofuran；0.1mL, 0.100mmol), kept for 5 DEG C of temperature <.It was dripped through about 10 minutes
Add pure (E) -3,3- dimethyl -1- nitro but-1-ene (2.09g, 16.18mmol) to be kept for 10 DEG C of temperature <.Addition is completed
Afterwards, reactant is continued to stir 25 minutes in ice bath.Then reaction mixture 25mL is saturated NH4The quenching of Cl solution and temperature
Heat is to room temperature.It is diluted with methyl tertiary butyl ether(MTBE), and with saturation NH4Cl aqueous solution washes twice, and is washed with brine primary.
By organic layer through Na2SO4It dries, filters, and is concentrated in a vacuum.Silica gel chromatography is (with 10% to 50% ethyl acetate-heptan
Alkane elution) provide title compound, 1.902g (32% yield).1H NMR (400MHz, DMSO-d6) δ ppm 7.42-7.34 (m,
1H), 7.30-7.17 (m, 2H), 7.08 (ddd, J=J=7.5,6.9,1.7Hz, 1H), 5.08 (dd, J=J=6.9,3.6Hz,
1H), 4.77 (d, J=J=6.9Hz, 1H), 4.23 (q, J=J=7.1Hz, 2H), 3.77 (d, J=J=7.6Hz, 1H), 3.25
(br s, 1H), 3.21-3.06 (m, 2H), 1.33-1.14 (m, 9H), 0.98 (s, 9H)；MS(ESI+)m/z 363.1(M+H)+。
Core 9
(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 9A
(E)-tert-butyl 2- ((2- isopropyl benzal) amino) acetic acid esters
At room temperature, to tert-butyl 2- amion acetic acid ester hydrochloride (2.55g, 14.74mmol) and magnesium sulfate (3.55g,
29.5mmol) in anhydrous CH2Cl2Triethylamine (2.158mL, 15.48mmol) is slowly added in stirred suspension in (50mL).
It stirs the mixture for 15 minutes, is handled with 2- propylbenzyl aldehyde (2.3g, 14.74mmol), and be stirred overnight.By solid material
It removes via filtering, and by filtrate water (quick wash is twice) and salt water washing, is then dried over sodium sulfate, filter and dense
Contracting, with offer (E)-tert-butyl 2- ((2- isopropyl benzal) amino) acetic acid esters (3.85g, 14.74mmol, 100% yield).1H
NMR (400MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 7.75 (dd, J=7.8,1.4Hz, 1H), 7.44-7.32 (m, 2H),
7.21 (ddd, J=8.1,7.0,1.7Hz, 1H), 4.30 (d, J=1.2Hz, 2H), 3.58 (hept, J=6.8Hz, 1H), 1.40
(s, 9H), 1.24-1.15 (m, 6H)；MS(DCI+)m/z 262.1(M+H)+。
Core 9B
(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.075g, 0.100mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.019g, 0.038mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 2 hours
In (11.83mL).Gained mixture is stirred at room temperature 1.5 hours, and is added after being cooled to 5 DEG C of < in ice-water bath pure
(E)-tert-butyl 2- ((2- isopropyl benzal) amino) acetic acid esters (2.01g, 7.69mmol).2- methyl propyl- 2- potassium alcoholate is added dropwise
(1M in tetrahydrofuran, 0.077mL, 0.077mmol), then through 25 minutes pure (E) -3,3- dimethyl -1- nitros of addition
But-1-ene (0.993g, 7.69mmol) is kept for 10 DEG C of internal temperature <.After the completion of addition, by reaction mixture in same temperature
Lower stirring 15 minutes.Reaction mixture is diluted with methyl tertiary butyl ether(MTBE) (60mL), and is saturated aqueous chlorine with 40mL at room temperature
Change ammonium to stir together 15 minutes.Organic layer is separated to and used saturation aqueous sodium bicarbonate and salt water washing, is dried over sodium sulfate, mistake
It filters and is concentrated.By residue by flash chromatography (0 to 30% ethyl acetate in heptane) purify, with offer (2S, 3R,
4S, 5S)-tert-butyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters (2.48g,
6.35mmol, 83% yield).1H NMR (501MHz, DMSO-d6) δ ppm7.35 (dd, J=7.9,1.4Hz, 1H), 7.31-
7.18 (m, 2H), 7.10 (ddd, J=8.5,7.3,1.5Hz, 1H), 5.08 (dd, J=7.0,3.6Hz, 1H), 4.70 (dd, J=
8.5,6.9Hz, 1H), 3.61 (t, J=7.7Hz, 1H), 3.40 (t, J=8.1Hz, 1H), 3.10 (hept, J=6.8Hz, 1H),
3.00 (dd, J=7.8,3.5Hz, 1H), 1.47 (s, 9H), 1.28 (d, J=6.8Hz, 3H), 1.16 (d, J=6.7Hz, 3H),
0.95 (s, 9H)；MS(ESI+)m/z 390.9(M+H)+。
Core 10
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (o-tolyl) pyrrolidines -2- formic acid esters
Core 10A
(E)-ethyl 2- ((2- methylbenzilidene) amino) acetic acid esters
At ambient temperature, by ethyl 2- amion acetic acid ester hydrochloride (3.97g, 28.5mmol) and magnesium sulfate (3.43g,
28.5mmol) the stirring in methylene chloride (43.1mL), and add triethylamine (3.97mL, 28.5mmol).Stir the mixture for 5
Simultaneously 2- tolyl aldehyde (2.97mL, 25.9mmol) is added dropwise in minute.Mixture is stirred at ambient temperature 16 hours.By solid
Material passes through disposable plastic frit and is washed with methylene chloride.It is dry through sodium sulphate by organic layer 30mL water washing
It is dry, it filters and is concentrated.1H NMR(500MHz, CDCl3) δ ppm 8.63 (d, J=J=1.4Hz, 1H), 7.96 (dd, J=J=
7.7,1.4Hz, 1H), 7.35 (td, J=J=7.5,1.5Hz, 1H), 7.32-7.25 (m, 1H), 7.25-7.18 (m, 1H),
4.45 (d, J=J=1.4Hz, 2H), 4.28 (q, J=J=7.2Hz, 2H), 2.55 (s, 3H), 1.34 (t, J=J=7.1Hz,
3H)；MS(ESI+)m/z 206(M+H)+。
Core 10B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (o-tolyl) pyrrolidines -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.222g, 0.294mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.064g, 0.127mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 4 hours
In (51.7mL).Gained mixture is stirred 1.5 hours at ambient temperature, and is added after being cooled to 5 DEG C of < in ice-water bath
(E)-ethyl 2- ((2- methylbenzilidene) amino) acetic acid esters (5.31g, 25.9mmol).2- methyl propyl- 2- potassium alcoholate is added dropwise, and (1M exists
In THF, 0.203mL, 0.203mmol), then through 25 minutes pure (E) -3,3- dimethyl -1- nitro but-1-enes of addition
(3.51g, 27.2mmol) is kept for 10 DEG C of internal temperature <.After the completion of addition, reactant is stirred to 90 points at the same temperature
Clock.Reaction mixture is diluted with methyl tertiary butyl ether(MTBE) (100mL), and is saturated aqueous ammonium chloride one with 50mL at ambient temperature
Play stirring 15 minutes.By organic layer saturation aqueous sodium bicarbonate and salt water washing, it is dried over sodium sulfate and filters.Filtrate is dense
Contracting is diluted to provide thick residue, by it with 80mL heptane, and reduces the volume of solvent until being settled out solid.Mixture is existed
It is cooled to 5 DEG C of < in ice bath and continues 15 minutes, and obtained solid filters, it is dry with 20mL heptane wash, and in vacuum drying oven
To constant weight, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (o-tolyl) pyrrolidines -2- formic acid esters
(4.85g, 14.50mmol, 56% yield).1H NMR (501MHz, CDCl3) δ ppm 7.34-7.27 (m, 1H), 7.27-7.16
(m, 3H), 5.18 (dd, J=J=61,2.6Hz, 1H), 4.55 (dd, J=J=10.1,5.9Hz, 1H), 4.35 (qd, J=J=
7.2,1.2Hz, 2H), 3.81 (t, J=J=7.1Hz, 1H), 3.31 (s, 1H), 3.07 (dd, J=J=7.3,2.6Hz, 1H),
2.41 (s, 3H), 1.38 (t, J==7.1Hz, 3H), 1.08 (s, 9H).MS(APCI+)m/z 335(M+H)+。
Core 11
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro-pyrrole
Alkane -2- formic acid esters
Core 11A
(E)-ethyl 2- (((2- (dimethylamino) pyridin-3-yl) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (6.08g, 43.6mmol) and magnesium sulfate (9.99g, 83mmol) are suspended in
In methylene chloride (69.1mL), and by suspension 2- (dimethylamino) cigarette aldehyde (6.23g, 41.5mmol) and triethylamine
(5.78mL, 41.5mmol) processing.Mixture is stirred at ambient temperature 16 hours.Solid material is removed via filtering,
And wash filtrate water (2x20mL), it is dried over sodium sulfate, filters and be concentrated to provide title compound, by it without in addition
Purifying i.e. use.1H NMR (400MHz, chloroform-d) δ ppm 8.42-8.37 (m, 1H), 8.26 (dd, J=4.8,2.0Hz,
1H), 8.06 (dd, J=7.6,1.9Hz, 1H), 6.84 (ddd, J=7.6,4.8,0.6Hz, 1H), 4.40 (d, J=1.3Hz,
2H), 4.23 (q, J=7.1Hz, 2H), 2.97 (s, 6H), 1.29 (t, J=7.1Hz, 3H).
Core 11B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro-pyrrole
Alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphines) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2- base)
Amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.317g, 0.421mmol) and copper trifluoromethanesulfcomposite (I)
Dimer benzene complex (0.091g, 0.181mmol), which is dissolved in, has used N2Stream sprays in 1 hour tetrahydrofuran (43.0mL).
Gained mixture is stirred 1 hour at ambient temperature.Disposable addition core 11A (5.47g, 23.23mmol) is in 3mL tetrahydro furan
Solution in muttering, and flask is cooled to 5 DEG C of < in ice-water bath.Be added dropwise 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran,
0.290mL, 0.290mmol), then through 10 minutes addition (E) -3,3- dimethyl -1- nitro but-1-enes (2.5g,
19.36mmol) the solution in 2mL tetrahydrofuran keeps temperature to be lower than 7 DEG C.Pass through LC/MS immediately after adding nitroolefin
Reaction mixture is measured, is shown complete conversion.Reaction 5mL is saturated aqueous ammonium chloride to quench, environment temperature is warmed to, uses
Methyl tertiary butyl ether(MTBE) (50mL) dilution, and with aqueous ammonium chloride (2x20mL) is saturated, then salt water (20mL) dilutes, and through sulfuric acid
Sodium is dry.After filtering, filtrate is concentrated in a vacuum to provide thick residue, by it with 10: 90 to 100 on 120g silicagel column
: 0 methyl tertiary butyl ether(MTBE): heptane carries out chromatography 20 minutes, to provide the title compound of 5.97g.1H NMR (501MHz, chloroform-
D) δ ppm 8.30 (dd, J=4.8,1.8Hz, 1H), 7.62 (ddd, J=7.6,1.8,0.8Hz, 1H), 6.99 (dd, J=7.7,
4.8Hz, 1H), 5.48 (dd, J=5.7,2.4Hz, 1H), 4.62 (dd, J=12.3,5.7Hz, 1H), 4.31 (qd, J=72,
1.6Hz, 2H), 3.80 (dd, J=9.7,7.1Hz, 1H), 3.18 (t, J=11.2Hz, 1H), 2.94-2.90 (m, 1H), 2.79
(s, 6H), 1.34 (t, J=7.1Hz, 3H), 1.07 (s, 10H)；MS(ESI+)m/z 365.2(M+H)+。
Core 12
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- methoxypyridine -3- base) -4- nitro-pyrrole alkane -2- first
Acid esters
Core 12A
(E)-ethyl 2- (((2- methoxypyridine -3- base) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (14.50g, 104mmol) and magnesium sulfate (20.01g, 166mmol) are suspended
In 130mL methylene chloride.Solution of the 2- methoxyl group cigarette aldehyde (11.4g, 83mmol) in 9mL methylene chloride is added to stirring
In mixture, then adds triethylamine (14.48mL, 104mmol) and stir reaction mixture at ambient temperature 16 hours.
Solid material is removed via filtering, and by filtrate cold water (2x10mL) and salt water (10mL) quick wash, is done through sodium sulphate
It is dry, it filters and is concentrated to provide thick imines, it is used without other purifying.1H NMR (500MHz, DMSO-d6)δppm
8.58 (d, J=1.6Hz, 1H), 8.31 (dd, J=4.9,2.0Hz, 1H), 8.19 (dd, J=7.4,2.0Hz, 1H), 7.09
(ddd, J=7.4,4.9,0.7Hz, 1H), 4.45 (d, J=1.4Hz, 2H), 4.14 (q, J=7.2Hz, 2H), 3.96 (s, 3H),
1.22 (t, J=7.1Hz, 3H).
Core 12B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- methoxypyridine -3- base) -4- nitro-pyrrole alkane -2- first
Acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.642g, 0.853mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.185g, 0.367mmol), which is dissolved in, has used N2Stream sprays 4 hours tetrahydrofurans (150mL)
In.Gained mixture is stirred 1.5 hours at ambient temperature, and cooling flask to internal temperature is 5 DEG C of < in ice-water bath
By added by syringe (E)-ethyl 2- (((2- methoxypyridine -3- base) methylene) amino) acetic acid esters (17.50g,
79mmol).2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.588mL, 0.588mmol) is added dropwise via syringe, then
Via syringe through 25 minutes pure (E) -3,3- dimethyl -1- nitro but-1-enes (9.69g, 75.0mmol) of addition, in holding
10 DEG C of portion temperature <.Reaction mixture is stirred at the same temperature 20 minutes, LC-MS shows that nitroolefin disappears completely at this time
Consumption.Reaction mixture is diluted with methyl tertiary butyl ether(MTBE) (300mL), and is saturated aqueous ammonium chloride with 300mL at ambient temperature
It stirs 15 minutes together.These layers are separated, and by organic layer saturation aqueous sodium bicarbonate and salt water washing, are done through sodium sulphate
It is dry, it filters and is concentrated to provide thick residue, by it through Silica gel chromatography, with 0: 100 to 50: 50 acetic acid on 330g column
Ethyl ester: heptane elutes 30 minutes, to provide the title compound of 17.5g.1H NMR (400MHz, CDCl3) δ ppm 8.13 (dd, J
=5.0,1.5Hz, 1H), 7.62-7.34 (m, 1H), 6.96-6.71 (m, 1H), 5.36 (dt, J=5.7,1.8Hz, 1H),
4.54-4.38 (m, 1H), 4.41-4.25 (m, 2H), 4.04 (s, 3H), 3.82-3.65 (m, 1H), 3.28 (s, 1H), 2.93
(dt, J=7.3,1.8Hz, 1H), 1.37 (td, J=7.2,1.2Hz, 3H), 1.08 (s, 9H)；MS(ESI+)m/z 352.1(M+
H)+。
Core 13
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropoxypyrid -3- base) -4- nitro-pyrrole alkane -2-
Formic acid esters
Core 13A
(E)-ethyl 2- (((2- isopropoxypyrid -3- base) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (4.97g, 35.6mmol) and magnesium sulfate (6.86g, 57.0mmol) are suspended
In methylene chloride (47.5mL), and by suspension 2- isopropoxy cigarette aldehyde (4.8g, 28.5mmol) and triethylamine
(4.96mL, 35.6mmol) processing.Mixture is stirred at room temperature 16 hours.Solid material via filtering removal and will be filtered
Liquid water (twice) and salt water washing, are dried over sodium sulfate, and filter and are concentrated to provide thick (E)-ethyl 2- (((2- isopropyl oxygen
Yl pyridines -3- base) methylene) amino) acetic acid esters (7.14g, 28.5mmol, 100% yield), be without other purifying by it
It uses.1H NMR (400MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 8.25 (dd, J=4.9,2.0Hz, 1H), 8.13 (dd, J
=7.5,2.1Hz, 1H), 7.00 (ddd, J=7.5,4.9,0.7Hz, 1H), 5.34 (hept, J=6.2Hz, 1H), 4.41 (d, J
=1.3Hz, 2H), 4.15-3.99 (m, 2H), 1.30 (d, J=6.2Hz, 6H), 1.18 (t, J=7.1Hz, 3H)；MS(DCI+)
m/z 251.0(M+H)+。
Core 13B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropoxypyrid -3- base) -4- nitro-pyrrole alkane -2-
Formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.141g, 0.187mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.036g, 0.072mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 2 hours
In (22.13mL).Gained mixture is stirred at room temperature 1.5 hours, and is added after being cooled to 5 DEG C of < in ice-water bath pure
(E)-ethyl 2- (((2- isopropoxypyrid -3- base) methylene) amino) acetic acid esters (3.6g, 14.38mmol).2- first is added dropwise
Base propan-2-ol potassium (1M in tetrahydrofuran, 0.144mL, 0.144mmol), then through 25 minutes pure (E) -3,3- bis- of addition
Methyl-1-nitro but-1-ene (1.858g, 14.38mmol) is kept for 10 DEG C of internal temperature <.After the completion of addition, reaction is mixed
Object stirs 15 minutes at the same temperature.By reaction mixture with methyl tertiary butyl ether(MTBE) (100mL) dilute, and at room temperature with
75mL is saturated aqueous ammonium chloride and stirs together 15 minutes.Organic layer is separated and is used saturated sodium bicarbonate aqueous solution and salt wash
It washs, is dried over sodium sulfate, filter and be concentrated.Residue is passed through into flash chromatography (0 to 20% ethyl acetate in heptane)
Purifying, to provide title compound (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropoxypyrid -3- base) -4-
Nitro-pyrrole alkane -2- formic acid esters (4.51g, 11.89mmol, 83% yield).1H NMR (400MHz, DMSO-d6)δppm 8.04
(dd, J=5.0,1.8Hz, 1H), 7.64 (dt, J=7.4,1.4Hz, 1H), 6.90 (dd, J=7.3,5.0Hz, 1H), 5.33-
5.19 (m, 2H), 4.41 (dd, J=9.5,6.1Hz, 1H), 4.19 (qd, J=7.1,5.3Hz, 2H), 3.77 (dd, J=8.4,
7.3Hz, 1H), 3.55 (t, J=8.9Hz, 1H), 2.92 (dd, J=7.3,2.6Hz, 1H), 1.32 (dd, J=13.6,6.1Hz,
6H), 1.23 (t, J=7.1Hz, 3H), 0.95 (s, 9H)；MS(ESI+)m/z 380.0(M+H)+。
Core 14
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 14A
(E)-ethyl 2- ((2- cyclopropyl benzal) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (4.50g, 32.2mmol) and magnesium sulfate (6.21g, 51.6mmol) are suspended
It is handled in methylene chloride (43.0mL), and by suspension with triethylamine (4.49mL, 32.2mmol).After 1 hour, addition exists
2- cyclopropyl-phenyl formaldehyde (3.77g, 25.8mmol) in 5mL methylene chloride, and reaction is stirred at room temperature 16 hours.It will consolidate
Body material is dried over sodium sulfate via filtering removal and by filtrate water and salt water washing, filters and be concentrated with offer (E)-second
Base 2- ((2- cyclopropyl benzal) amino) acetic acid esters (5.68g, 24.56mmol, 95% yield), without further purification by it
I.e. in next step.1H NMR (400MHz, DMSO-d6) δ ppm8.92 (d, J=1.5Hz, 1H), 7.81 (dd, J=7.8,
1.5Hz, 1H), 7.35 (td, J=7.6,1.5Hz, 1H), 7.22 (td, J=7.6,1.2Hz, 1H), 7.05 (dd, J=7.8,
1.2Hz, 1H), 4.45 (d, J=1.3Hz, 2H), 4.13 (q, J=7.1Hz, 2H), 2.33 (tt, J=8.5,5.3Hz, 1H),
1.21 (t, J=7.1Hz, 3H), 1.03-0.90 (m, 2H), 0.75-0.63 (m, 2H)；MS(ESI+)m/z 232.1(M+H)+。
Core 14B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.241g, 0.319mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.062g, 0.123mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 2 hours
In (63.0mL).Gained mixture is stirred at room temperature 1.5 hours, and is added after being cooled to 5 DEG C of < in ice-water bath four
(E)-ethyl 2- ((2- cyclopropyl benzal) amino) acetic acid esters (5.68g, 24.56mmol) in hydrogen furans (8mL).2- is added dropwise
Methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.246mL, 0.246mmol), then through addition pure (E) -3,3- in 25 minutes
Dimethyl -1- nitro but-1-ene (3.17g, 24.56mmol) is kept for 10 DEG C of internal temperature <.After the completion of addition, reaction is existed
It is stirred 15 minutes under same temperature, diluted with methyl tertiary butyl ether(MTBE) (100mL) and is saturated aqueous ammonium chloride at room temperature with 75mL
Stirring 15 minutes.Organic layer is separated, with saturation aqueous sodium bicarbonate and salt water washing, is dried over sodium sulfate and filters.It will filter
Liquid is concentrated and passes through flash chromatography (0 to 30% ethyl acetate in heptane) purifying, with offer (2S, 3R, 4S, 5S)-second
Base 3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters (6.85g, 19.00mmol, 77%
Rate), ee > 97%.1H NMR (501MHz, DMSO-d6) δ ppm7.34 (dd, J=7.6,1.5Hz, 1H), 7.15 (dtd, J=
25.3,7.5,1.6Hz, 2H), 7.07-7.01 (m, 1H), 5.31 (dd, J=6.7,3.1Hz, 1H), 4.92 (dd, J=8.4,
6.6Hz, 1H), 4.27-4.12 (m, 2H), 3.75 (t, J=7.7Hz, 1H), 3.51 (t, J=8.1Hz, 1H), 3.04 (dd, J=
7.6,3.1Hz, 1H), 2.06 (tt, J=8.5,5.4Hz, 1H), 1.24 (t, J=7.1Hz, 3H), 0.95 (s, 9H), 1.00-
0.78 (m, 2H), 0.81-0.68 (m, 1H), 0.64-0.55 (m, 1H)；MS(ESI+)m/z 361.2(M+H)+。
Core 15
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoro-methoxy) phenyl) -4- nitro-pyrrole alkane -2- first
Acid esters
Core 15A
(E)-ethyl 2- ((2- (difluoro-methoxy) benzal) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (2.5g, 17.91mmol) and magnesium sulfate (2.156g, 17.91mmol) is outstanding
Float in methylene chloride (23mL).It adds triethylamine (2.496mL, 17.91mmol), and at ambient temperature by reaction mixture
2- (difluoro-methoxy) benzaldehyde (2.57g, 14.93mmol) is added in stirring 1 hour later.Reaction is stirred at ambient temperature
It mixes overnight.Solid material is removed using sinter funnel via filtering, and filter cake is washed with methylene chloride (10mL).By filtrate
The salt water quick wash of 10mL then is used with the water of 2x10mL, and is dried over sodium sulfate, filters and is concentrated to provide title compound
Object (3.07g) uses it without other purifying.1H NMR (501MHz, chloroform-d) δ ppm 8.64 (s, 1H), 8.12
(dd, J=7.8,1.8Hz, 1H), 7.45 (ddd, J=8.2,7.4,1.8Hz, 1H), 7.34-7.23 (m, 1H), 7.15 (dq, J
=8.2,1.1Hz, 1H), 6.58 (t, J=73.5Hz, 1H), 4.43 (d, J=1.3Hz, 2H), 4.27 (q, J=7.1Hz, 2H),
1.31 (t, J=7.2Hz, 3H).
Core 15B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoro-methoxy) phenyl) -4- nitro-pyrrole alkane -2- first
Acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphines) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2- base)
Amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.126g, 0.168mmol) and copper trifluoromethanesulfcomposite (I)
Dimer benzene complex (0.037g, 0.073mmol), which is dissolved in, has used N2Stream sprays 20 minutes tetrahydrofurans (21.60mL)
In.Acquired solution is stirred 1 hour at ambient temperature, and addedMolecular sieve (3g, 9.72mmol) then adds (E)-
Ethyl 2- ((2- (difluoro-methoxy) benzal) amino) solution of acetic acid esters (3g, 11.66mmol) in 3mL tetrahydrofuran,
And gained suspension is cooled to 5 DEG C of < in ice-water bath.Be added dropwise 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran,
0.117mL, 0.117mmol), then through 5 minutes addition (E) -3,3- dimethyl -1- nitro but-1-enes (1.255g,
9.72mmol) the solution in 2mL tetrahydrofuran keeps temperature to be lower than 8 DEG C.Pass through LC-MS immediately after adding nitroolefin
Reaction mixture is measured, visualizingre agent completely consumes.Reaction mixture 5mL is saturated aqueous ammonium chloride and 5mL water is sudden
It goes out, is then stirred at room temperature 5 minutes.Solid is removed by diatomite via filtering, and by filtrate methyl tertiary butyl ether(MTBE)
(30mL) dilution.These layers are separated, and organic layer is washed with the aqueous ammonium chloride (2x20mL) of saturation and salt water (20mL), and
It is dried over sodium sulfate, filters and is concentrated.It adds heptane (30mL), and it is small that gained suspension is vigorously stirred 1 at ambient temperature
When.Obtained solid is removed using sinter funnel via filtering, and is dried in 40 DEG C of vacuum drying ovens to constant weight, to provide
2.94g title compound.1H NMR (400MHz, chloroform-d) δ ppm 7.42-7.27 (m, 2H), 7.21 (td, J=7.6,
1.1Hz, 1H), 7.07 (dd, J=8.1,1.4Hz, 1H), 6.57 (dd, J=76.4,70.9Hz, 1H), 5.30 (dd, J=5.8,
2.3Hz, 1H), 4.61 (dd, J=12.6,5.8Hz, 1H), 4.32 (qd, J=7.2,1.5Hz, 2H), 3.80 (dd, J=9.8,
7.1Hz, 1H), 3.27 (dd, J=12.6,10.0Hz, 1H), 2.95 (dd, J=7.1,2.3Hz, 1H), 1.35 (t, J=
7.2Hz, 3H), 1.05 (s, 9H)；MS(ESI+)m/z 387.1(M+H)+。
Core 16
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoro-methoxy) pyridin-3-yl) -4- nitro-pyrrole
Alkane -2- formic acid esters
Core 16A
3- bromo- 2- (difluoro-methoxy) pyridine
3- bromopyridine -2- alcohol (13g, 72.5mmol) is dissolved in acetonitrile (362mL).Add 2,2-, bis- fluoro- 2- (fluorine sulphonyl
Base) acetic acid (15.49g, 87mmol) and sodium sulphate (11.32g, 80mmol).Mixture is stirred at room temperature 16 hours, second is used
Acetoacetic ester dilution, and these layers are separated.Aqueous layer with ethyl acetate is extracted, and combined extract is saturated aqueous carbonic acid
Hydrogen sodium, water and salt water washing.Organic matter is dried over sodium sulfate, filters and is concentrated to provide about 20g crude product, by it via fast
Speed is column chromatography eluting, is eluted on 120g silicagel column with 0-15% methyl tertiary butyl ether(MTBE)/heptane, to provide title compound 3-
Bromo- 2- (difluoro-methoxy) pyridine (13.21g, 59.0mmol, 81% yield).1H NMR (400MHz, DMSO-d6)δppm
8.36-8.13 (m, 2H), 7.71 (td, J=72.2,1.2Hz, 1H), 7.22 (ddd, J=7.8,4.8,1.1Hz, 1H)；MS
(DCI+)m/z 225.8(M+H)+。
Core 16B
Methyl 2- (difluoro-methoxy) nicotinate
To 3- bromo- 2- (difluoro-methoxy) pyridine (17.51g, 78mmol), the Pd-dppf in 180mL SS reactor
(Heraeus) addition methanol (50mL) and triethylamine (20mL, 143mmol) in (0.572g, 0.782mmol).Reactor is used
Argon-degassed for several times, fills carbon monoxide and is heated to 132 DEG C at 119psi CO and continues 10 minutes.Stop heating and reducing
Pressure gauge setting.Reaction mixture is stirred overnight under CO gas, it is cooling simultaneously.HPLC shows that starting material has consumed.It will
Mixture is concentrated and distributes between water and ethyl acetate.Combined extract is washed with brine, is dried over sodium sulfate, is filtered
And be concentrated to provide crude product methyl 2- (difluoro-methoxy) nicotinate (15.3g, 75.3mmol, 96% yield), by its without
In addition purifying uses.1H NMR (500MHz, DMSO-d6) δ ppm 8.45 (dd, J=4.9,1.9Hz, 1H), 8.31 (dd, J
=7.6,2.0Hz, 1H), 7.93-7.55 (m, 1H), 7.39 (dd, J=7.6,4.9Hz, 1H), 3.85 (s, 3H).
Core 16C
(2- (difluoro-methoxy) pyridin-3-yl) methanol
Methyl 2- (difluoro-methoxy) nicotinate (4.72g, 2323mmol) is dissolved in 100mL tetrahydrofuran.It is cooled to
After 5 DEG C of <, the solution of lithium aluminium hydride reduction (18.82mL, 18.82mmol) in tetrahydrofuran is added within 10 minutes, keeps internal temperature
10 DEG C of < of degree.HPLC and LC-MS is converted completely after showing 30 minutes.Reaction mixture is cooled to 0 DEG C, and by reaction by adding
Add 3mL acetone to quench, then diluted with ethyl acetate (100mL) and is saturated aqueous sodium potassium tartrate tetrahydrate (Rochelle salt) one with 80mL
Stirring 1 hour is played, to provide two clear layers.Mixture is diluted with ethyl acetate and separates these layers.By organic layer
Be washed with brine, be dried over sodium sulfate, filter and be concentrated with offer (2- (difluoro-methoxy) pyridin-3-yl) methanol (4.07g,
23.24mmol, 100% yield).1H NMR (501MHz, DMSO-d6) δ ppm 8.15-8.05 (m, 1H), 7.91 (ddt, J=
7.3,1.9,1.0Hz, 1H), 7.69 (t, J=73.0Hz, 1H), 7.26 (dd, J=7.4,4.9Hz, 1H), 5.37 (t, J=
5.6Hz, 1H), 4.53-4.36 (m, 2H)；MS(ESI+)m/z 175.9(M+H)+。
Core 16D
2- (difluoro-methoxy) cigarette aldehyde
(2- (difluoro-methoxy) pyridin-3-yl) methanol (4.07g, 23.24mmol) is dissolved in methylene chloride (93mL).
After being cooled to 5 DEG C of < in ice-water bath, Dai Si-Martin is added batch-wise and crosses iodine alkane (11.83g, 27.9mmol), keeps internal temperature
20 DEG C of <.After the completion of addition, flask is warmed to room temperature lasting 15 minutes, reaction is completed at this time.By mixture 250mL methyl
Tertbutyl ether dilution, and 15 points are stirred with saturation aqueous sodium bicarbonate (80mL) and saturated sodium thiosulfate (80mL) at room temperature
Clock.These layers are separated, and water layer is extracted with methyl tertiary butyl ether(MTBE) (2x150mL).Combined organic layer is washed with brine
Then it is concentrated, and is purified via quick column (0 to 20% ethyl acetate in heptane), to provide title compound 2- (difluoro
Methoxyl group) cigarette aldehyde (2.38g, 13.75mmol, 59.2% yield).1H NMR (501MHz, DMSO-d6) δ ppm 10.20 (s,
1H), 8.53 (dd, J=4.9,2.0Hz, 1H), 8.27 (dd, J=7.6,2.0Hz, 1H), 7.83 (t, J=73.0Hz, 1H),
7.45 (ddd, J=7.6,4.9,0.8Hz, 1H)；MS(DCI+)m/z 190.9(M+NH4)+。
Core 16E
(E)-ethyl 2- (((2- (difluoro-methoxy) pyridin-3-yl) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (2.399g, 17.18mmol) and magnesium sulfate (3.31g, 27.5mmol) is outstanding
Float in methylene chloride (22.91mL), and suspension is handled with triethylamine (2.395mL, 17.18mmol).Mixture is existed
It stirs 1 hour at room temperature, and adds 2- (difluoro-methoxy) the cigarette aldehyde (2.38g, 13.75mmol) in 5mL methylene chloride.It will
Mixture is stirred at room temperature 16 hours.Thin-layer chromatography (30% ethyl acetate containing 5% triethylamine in heptane) display reaction
It completes.Solid material is removed via filtering, and by filtrate water (quick wash is twice) and salt water washing, is done through sodium sulphate
It is dry, it filters and is concentrated with offer (E)-ethyl 2- (((2- (difluoro-methoxy) pyridin-3-yl) methylene) amino) acetic acid esters
(3.5g, 13.55mmol, 99% yield).1H NMR (501MHz, DMSO-d6) δ ppm 8.55 (dt, J=1.5,0.9Hz, 1H),
8.40-8.31 (m, 2H), 7.93-7.64 (m, 1H), 7.36 (ddd, J=7.6,4.8,0.7Hz, 1H), 4.50 (d, J=
1.4Hz, 2H), 4.13 (q, J=7.1Hz, 2H), 1.24-1.12 (t, J=7.1Hz, 3H)；MS(DCI+)m/z 259.0(M+H)+。
Core 16F
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoro-methoxy) pyridin-3-yl) -4- nitro-pyrrole
Alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.133g, 0.176mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.034g, 0.068mmol), which is dissolved in, has used N2Stream sprays 4 hours tetrahydrofuran (tetrahydro furans
Mutter) in (30mL).Gained mixture is stirred at room temperature 1.5 hours, and is added after being cooled to 5 DEG C of < in ice-water bath four
In hydrogen furans (8mL) (E)-ethyl 2- (((2- (difluoro-methoxy) pyridin-3-yl) methylene) amino) acetic acid esters (3.5g,
13.55mmol).2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.136mL, 0.136mmol) is added dropwise, then through 25 minutes
Pure (E) -3,3- dimethyl -1- nitro but-1-ene (1.751g, 13.55mmol) is added, is kept for 10 DEG C of internal temperature <.Add
After the completion of adding, reaction mixture is stirred at the same temperature 15 minutes, LC-MS display reaction is completed.By mixture methyl
Tertbutyl ether (100mL) dilution, and stirred 15 minutes together with the aqueous ammonium chloride of 75mL saturation at room temperature.By these layers point
From, and organic layer is saturated aqueous sodium bicarbonate and salt water washing and is dried over sodium sulfate.After filtering, filtrate is concentrated and is led to
Flash column chromatography (0 to 30% ethyl acetate in heptane) purifying is crossed, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tertiary fourth
Base) -5- (2- (difluoro-methoxy) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters (3.95g, 10.20mmol, 75%
Rate).1H NMR (400MHz, DMSO-d6) δ ppm 8.17 (dd, J=5.0,1.8Hz, 1H), 7.95-7.88 (m, 1H), 7.25
(dd, J=7.6,4.9Hz, 1H), 5.15 (dd, J=6.6,3.0Hz, 1H), 4.59 (t, J=7.2Hz, 1H), 4.19 (qd, J=
7.1,3.8Hz, 2H), 3.80 (t, J=7.4Hz, 1H), 3.71 (t, J=7.7Hz, 1H), 3.04 (dd, J=7.4,3.1Hz,
1H), 1.24 (t, J=7.1Hz, 3H), 0.94 (s, 9H)；MS(ESI+)m/z 388.1(M+H)+。
Core 17
(2S, 3R, 4S, 5S)-ethyl 5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tert-butyl) -4- nitro
Pyrrolidines -2- formic acid esters
Core 17A
2- (azetidine -1- base) cigarette aldehyde
Into 40mL bottle add azetidine hydrochloride (0.412g, 4.40mmol), 2- chlorine cigarette aldehyde (0.53g,
3.67mmol)、K2CO3(1.268g, 9.17mmol) and dimethyl sulfoxide (DMSO) (7.34mL).Mixture is stirred at 110 DEG C
It mixes 20 hours.Saturated ammonium chloride is added, and mixture is extracted with ethyl acetate.Combined organic layer is washed with brine, is passed through
Na2SO4It dries, filters, be concentrated and purified by flash column chromatography (0 to 30% ethyl acetate in heptane), to provide 2-
(azetidine -1- base) cigarette aldehyde (0.52g, 3.21mmol, 87% yield).1H NMR (400MHz, DMSO-d6)δppm 9.86
(s, 1H), 8.29 (dd, J=4.6,1.9Hz, 1H), 7.96 (dd, J=7.6,1.9Hz, 1H), 6.75 (dd, J=7.6,
4.6Hz, 1H), 4.09 (d, J=15.2Hz, 3H), 3.29 (s, 2H), 2.37-2.24 (m, 3H)；MS(ESI+)m/z 163.0(M
+H)+。
Core 17B
(E)-ethyl 2- (((2- (azetidine -1- base) pyridin-3-yl) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (3.68g, 26.4mmol) and magnesium sulfate (5.08g, 42.2mmol) are suspended
It is handled in methylene chloride (35.1mL), and by suspension with triethylamine (3.67mL, 26.4mmol).At room temperature by mixture
Stirring 1 hour, then adds 2- (azetidine -1- base) cigarette aldehyde (3.42g, 21.09mmol) in 20mL methylene chloride.
Mixture is stirred at room temperature overnight.Thin-layer chromatography (30% ethyl acetate in the heptane containing 5% triethylamine) display is anti-
It should complete.Solid material is removed via filtering, and by filtrate water (quick wash is twice) and salt water washing, is done through sodium sulphate
It is dry, it filters and is concentrated with offer (E)-ethyl 2- (((2- (azetidine -1- base) pyridin-3-yl) methylene) amino) acetic acid
Ester (5.13g, 20.74mmol, 98% yield).1H NMR (400MHz, DMSO-d6) δ ppm 8.37 (s, 1H), 8.17 (dd, J=
4.7,1.9Hz, 1H), 7.89 (dd, J=7.6,1.9Hz, 1H), 6.74 (dd, J=7.5,4.7Hz, 1H), 4.38 (d, J=
1.2Hz, 2H), 4.16-4.02 (m, 6H), 2.28 (dq, J=8.2,7.3Hz, 2H), 1.19 (t, J=7.1Hz, 3H)；MS(ESI+)m/z 248.0(M+H)+。
Core 17C
(2S, 3R, 4S, 5S)-ethyl 5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tert-butyl) -4- nitro
Pyrrolidines -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.099g, 0.131mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.025g, 0.051mmol), which is dissolved in, has used N2Stream sprays 4 hours tetrahydrofurans (25.9mL)
In.Gained mixture is stirred at room temperature 1.5 hours, and is added after being cooled to 5 DEG C of < in ice-water bath in tetrahydrofuran
Core 17B in (8mL).2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.101mL, 0.101mmol) is added dropwise, then through 25
Minute adds pure (E) -3,3- dimethyl -1- nitro but-1-ene (1.306g, 10.11mmol), keeps internal temperature < 10
℃.After the completion of addition, reactant is stirred at the same temperature 15 minutes.Mixture is dilute with methyl tertiary butyl ether(MTBE) (50mL)
It releases, and is stirred 15 minutes together with the aqueous ammonium chloride of 25mL saturation at room temperature.Organic layer is separated and uses the aqueous carbonic acid of saturation
Hydrogen sodium and salt water washing, are dried over sodium sulfate, and filter and are concentrated.By residue by flash column chromatography (in heptane 0 to
30% ethyl acetate) purifying, with offer (2S, 3R, 4S, 5S)-ethyl 5- (2- (azetidine -1- base) pyridin-3-yl) -3-
(tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters (3.04g, 8.08mmol, 80% yield).1H NMR (500MHz, DMSO-d6)
δ ppm 8.03 (dd, J=4.7,1.8Hz, 1H), 7.60 (dd, J=7.6,1.8Hz, 1H), 6.67 (dd, J=7.6,4.8Hz,
1H), 5.08 (dd, J=7.1,3.7Hz, 1H), 4.46 (t, J=7.0Hz, 1H), 4.25-4.06 (m, 4H), 4.03 (dq, J=
9.6,7.3Hz, 2H), 3.70 (dd, J=8.1,6.9Hz, 1H), 3.49 (t, J=6.9Hz, 1H), 3.13 (dd, J=8.1,
3.7Hz, 1H), 2.29 (p, J=7.5Hz, 2H), 1.24 (d, J=7.1Hz, 3H), 0.93 (s, 9H)；MS(ESI+)m/z
377.2(M+H)+。
Core 18
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (2- (trifluoromethyl) pyridin-3-yl) pyrrolidines -
2- formic acid esters
Core 18A
(E)-ethyl 2- (((2- (trifluoromethyl) pyridin-3-yl) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (3.49g, 24.98mmol) and magnesium sulfate (4.81g, 40.0mmol) are suspended
It is handled in methylene chloride (33.3mL), and by suspension with triethylamine (3.48mL, 24.98mmol).After 1 hour, addition exists
2- (trifluoromethyl) cigarette aldehyde (3.5g, 19.99mmol) in methylene chloride (5mL), and reaction mixture is stirred at room temperature
16 hours.Solid material is removed via filtering, and by filtrate water and salt water washing, is dried over sodium sulfate, filters and be concentrated
With offer (E)-ethyl 2- (((2- (trifluoromethyl) pyridin-3-yl) methylene) amino) acetic acid esters (5.08g, 19.52mmol,
98% yield), it is used without further purification.1H NMR (400MHz, DMSO-d6) δ ppm 8.80 (dd, J=4.6,
1.6Hz, 1H), 8.68 (td, J=2.5,1.4Hz, 1H), 8.62-8.45 (m, 1H), 7.87-7.62 (m, 1H), 4.56 (d, J=
1.3Hz, 2H), 4.13 (m, 2H), 1.19 (m, 3H)；MS(ESI+)m/z 261.0(M+H)+。
Core 18B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (2- (trifluoromethyl) pyridin-3-yl) pyrrolidines -
2- formic acid esters
Tetrahydrofuran (50mL) is added into 250mL flask.It is sprayed 2 hours with nitrogen stream, and adds that (2- is (double
(3,5- bis- (trifluoromethyl) phenyl) phosphino-) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2- base) amyl- 2,4- diene-of ring
1- yl) (amyl- 2, the 4- diene -1- base of ring) iron (0.191g, 0.254mmol) and copper trifluoromethanesulfcomposite (I) dimer benzene complex
(0.049g, 0.098mmol).Reaction mixture is sprayed 90 minutes with nitrogen stream at room temperature, and is cooled in ice-water bath
(E)-ethyl 2- (((2- (trifluoromethyl) pyridin-3-yl) methylene) amino) of the addition in tetrahydrofuran (8mL) after 5 DEG C of <
Acetic acid esters (5.08g, 19.52mmol).Be added dropwise 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.195mL,
0.195mmol), pure (E) -3,3- dimethyl -1- nitro but-1-ene (2.52g, 19.52mmol) then was added through 25 minutes,
Kept for 10 DEG C of internal temperature <.After the completion of addition, reaction mixture is stirred 15 minutes, it is dilute with methyl tertiary butyl ether(MTBE) (100mL)
It releases and is saturated aqueous ammonium chloride with 75mL and be stirred at room temperature 15 minutes.Organic layer is separated and use saturation aqueous sodium bicarbonate and
Salt water washing, is then dried over sodium sulfate.Mixture is filtered, is concentrated and by flash chromatography (0 to 30% in heptane
Ethyl acetate) purifying, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (2- (trifluoromethyl) pyridine -
3- yl) pyrrolidines -2- formic acid esters (4.56g, 11.71mmol, 60.0% yield).Ee=95.4%.1H NMR (501MHz,
DMSO-d6) δ ppm 8.65 (m, 1H), 8.27 (dd, J=8.1,1.5Hz, 1H), 7.72 (ddd, J=19.7,8.0,4.6Hz,
1H), 5.02 (dd, J=7.1,3.3Hz, 1H), 4.84 (t, J=6.5Hz, 1H), 4.20 (qq, J=7.0,3.7Hz, 2H),
3.94 (t, J=5.9Hz, 1H), 3.83 (dd, J=7.3,6.3Hz, 1H), 3.19 (dd, J=7.4,3.3Hz, 1H), 1.25 (t,
J=7.1Hz, 3H), 0.93 (s, 9H)；MS(ESI+)m/z 390.1(M+H)+。
Core 19
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- cyclopropyl pyridine -3- base) -4- nitro-pyrrole alkane -2- first
Acid esters
Core 19A
2- cyclopropyl cigarette aldehyde
Isosorbide-5-Nitrae-the dioxanes and stirring rod of 6mL are packed into 40mL bottle.Mixture nitrogen is deaerated 5 minutes.To small
Be packed into bottle 2- bromine cigarette aldehyde (240mg, 1.290mmol), cyclopropylboronic acid (222mg, 2.58mmol) and cesium fluoride (588mg,
3.87mmol).Bottle is deaerated with nitrogen again.Add PdCl2Simultaneously reaction mixture exists dppf (53.1mg, 0.065mmol)
Heated under nitrogen is to 100 DEG C.After the reaction was completed, mixture is cooled to room temperature.It adds ethyl acetate (30mL), and by mixture
Stirring 5 minutes, is filtered in silicagel pad with ethyl acetate, is concentrated, and via flash column chromatography (0 to 20% in heptane
Ethyl acetate) purifying, to provide 2- cyclopropyl cigarette aldehyde (170mg, 1.155mmol, 90% yield).1H NMR (501MHz,
DMSO-d6) δ ppm 10.40 (s, 1H), 8.61 (dd, J=4.7,1.8Hz, 1H), 8.10 (dd, J=7.8,1.9Hz, 1H),
7.33 (dd, J=7.9,4.8Hz, 1H), 3.08 (tt, J=8.0,4.7Hz, 1H), 1.18-0.90 (m, 4H)；MS(ESI+)m/z
148.0(M+H)+。
Core 19B
(E)-ethyl 2- (((2- cyclopropyl pyridine -3- base) methylene) amino) acetic acid esters
By ethyl 2- amion acetic acid ester hydrochloride (1.707g, 12.23mmol) and magnesium sulfate (2.355g, 19.57mmol)
It is suspended in methylene chloride (16.31mL), and suspension is handled with triethylamine (1.705mL, 12.23mmol).Reaction is stirred
It mixes 1 hour, adds the 2- cyclopropyl cigarette aldehyde (1.44g, 9.78mmol) in methylene chloride (5mL) later.By mixture in room
Temperature stirring 16 hours.Solid material is removed via filtering, and by filtrate water (quick wash is twice) and salt water washing, through sulphur
Sour sodium is dried, filtered and concentrated, to provide (E)-ethyl 2- (((2- cyclopropyl pyridine -3- base) methylene) amino) second of 3.5g
Acid esters (2.06g, 8.87mmol, 91% yield).1H NMR (500MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.49 (dd, J
=4.7,1.8Hz, 1H), 8.08 (dd, J=7.8,1.9Hz, 1H), 7.21 (dd, J=7.8,4.7Hz, 1H), 4.50 (d, J=
1.3Hz, 2H), 4.15 (q, J=7.1Hz, 2H), 2.71 (tt, J=8.0,4.7Hz, 1H), 1.22 (t, J=7.1Hz, 3H),
1.05 (tt, J=5.4,2.7Hz, 2H), 1.04-0.93 (m, 2H)；MS(ESI+)m/z 233.1(M+H)+。
Core 19C
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- cyclopropyl pyridine -3- base) -4- nitro-pyrrole alkane -2- first
Acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.087g, 0.115mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.022g, 0.044mmol), which is dissolved in, has used N2Stream sprays 4 hours tetrahydrofurans (22.74mL)
In.Gained mixture is stirred at room temperature 1.5 hours, and is added after being cooled to 5 DEG C of < in ice-water bath in tetrahydrofuran
(E)-ethyl 2- (((2- cyclopropyl pyridine -3- base) methylene) amino) acetic acid esters (2.06g, 8.87mmol) in (8mL).Drop
Add 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.089mL, 0.089mmol), then through addition pure (E)-in 25 minutes
3,3- dimethyl -1- nitro but-1-enes (1.145g, 8.87mmol) are kept for 10 DEG C of internal temperature <.After the completion of addition, it will mix
It closes object to stir at the same temperature 15 minutes, LC-MS display reaction is completed.Mixture is dilute with methyl tertiary butyl ether(MTBE) (50mL)
It releases, and is stirred 15 minutes together with the aqueous ammonium chloride of 25mL saturation at room temperature.Organic layer is separated, with the aqueous bicarbonate of saturation
Sodium and salt water washing, are dried over sodium sulfate, and filter and are concentrated.By residue by flash column chromatography (in heptane 0 to
30% ethyl acetate) purifying, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- cyclopropyl pyridine -3- base) -4-
Nitro-pyrrole alkane -2- formic acid esters (2.6g, 7.19mmol, 81% yield).1H NMR (400MHz, DMSO-d6)δppm 8.26
(dd, J=4.7,1.7Hz, 1H), 7.73 (dd, J=7.8,1.7Hz, 1H), 7.05 (dd, J=7.8,4.7Hz, 1H), 5.33
(dd, J=7.1,3.7Hz, 1H), 4.89 (t, J=7.2Hz, 1H), 4.18 (qd, J=7.1,2.9Hz, 2H), 3.84-3.70
(m, 1H), 3.62 (t, J=7.1Hz, 1H), 3.08 (dd, J=7.8,3.7Hz, 1H), 2.20 (tt, J=8.1,4.9Hz, 1H),
1.22 (t, J=7.1Hz, 3H), 1.07-0.86 (m, 4H), 0.93 (s, 9H)；MS(ESI+)m/z 362.1(M+H)+。
Core 20
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- picoline -3- base) -4- nitre
Base pyrrolidines -2- formic acid esters
Core 20A
(E)-ethyl 2- (((2- chloropyridine -3- base) methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (3.71g, 26.6mmol) and magnesium sulfate (6.39g, 53.1mmol) are suspended
In methylene chloride (44.3mL), and by suspension triethylamine (3.70mL, 26.6mmol) and 2- chlorine cigarette aldehyde (3.76g,
26.6mmol) processing.Mixture is stirred at room temperature 16 hours.Solid material is removed by filtration.By filtrate water
(50mL) washing, and organic matter is dried over sodium sulfate, it filters and is concentrated to provide thick imines, be without other purifying by it
It uses.1H NMR (400MHz, chloroform-d) δ ppm 8.67 (t, J=J=1.1Hz, 1H), 8.49-8.40 (m, 2H), 7.32
(ddd, J=J=7.7,4.7,0.8Hz, 1H), 4.48 (d, J=J=1.4Hz, 2H), 4.26 (q, J=J=7.1Hz, 2H),
1.32 (dd, J=J=7.5,6.9Hz, 3H)；MS(ESI+)m/z 227(M+H)+。
Core 20B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chloropyridine -3- base) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.310g, 0.412mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.106g, 0.211mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 1 hour
In (48.0mL).Gained mixture is stirred at room temperature 1 hour (continuing nitrogen jet), and is addedMolecular sieve (6.00g,
22.07mmol), then addition core 20A (6.00g, 26.5mmol) solution in 10mL tetrahydrofuran, and by gained suspension
5 DEG C of < are cooled in ice-water bath.2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.331mL, 0.331mmol) is added dropwise,
Then through 10 minutes addition (E) -3,3- dimethyl -1- nitro but-1-enes (2.85g, 22.07mmol), temperature is kept to be lower than 7
℃.After twenty minutes, then (E) -3,3- dimethyl -1- nitro but-1-ene of 150mg is added.Mixture 5mL is saturated aqueous chlorine
Change ammonium to quench and warm to room temperature, then be filtered by Celite pad to remove molecular sieve.Filtrate is dilute with methyl tertiary butyl ether(MTBE)
It releases, and with being saturated aqueous ammonium chloride (2x50mL) and salt water washing, and passes through silicagel pad filtering.By mixture concentration and use just oneself
Alkane dilution.It reduces the volume of solvent and grinds rough material until forming blocks of solid.By solvent be decanted and by obtained solid from
It is precipitated in the hot n-hexane of 100mL, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chloropyridine -3- base) -4-
Nitro-pyrrole alkane -2- formic acid esters (5.892g, 16.56mmol, 75% yield).1H NMR (501MHz, chloroform-d) δ ppm 8.37
(dd, J=J=4.7,1.9Hz, 1H), 7.81 (ddd, J=J=7.7,1.9,0.8Hz, 1H), 7.31-7.25 (m, 1H), 5.42
(dd, J=J=6.0,2.4Hz, 1H), 4.71 (dd, J=J=9.5,5.9Hz, 1H), 4.34 (qd, J=J=7.1,2.3Hz,
2H), 3.86 (t, J=J=6.9Hz, 1H), 3.16-3.09 (m, 1H), 3.07 (dd, J gas J=6.9,2.3Hz, 1H), 1.37
(t, J=J=7.2Hz, 3H), 1.10 (s, 9H)；MS(APCI+)m/z 356(M+H)+.It is confirmed absolutely by X-ray analysis
Spatial chemistry.
Core 20C
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chloropyridine -3- base) -1- (cyclohexane carbo) -4- nitro
Pyrrolidines -2- formic acid esters
Core 20B (1.034g, 2.91mmol) is dissolved in methylene chloride (5mL), and adds N- ethyl-N-iospropyl propyl-
Cyclohexanecarbonyl chloride (0.447g, 3.05mmol) is then added dropwise in methylene chloride (5mL) in 2- amine (1.269mL, 7.26mmol)
Solution.Reaction is stirred at room temperature 4 hours.Then reaction is diluted with water, and be extracted with dichloromethane.By combined extraction
Object is dried over sodium sulfate, and is filtered, concentration, and it is pure to use 80g silicagel column to be carried out with the gradient of 5%-100% ethyl acetate/heptane
Change 20 minutes, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chloropyridine -3- base) -1- (cyclohexane carbo) -
4- nitro-pyrrole alkane -2- formic acid esters (0.675g, 1.449mmol, 49.8% yield).1H NMR (400MHz, DMSO-d6, 120
DEG C) δ ppm 8.29 (dd, J=J=4.7,1.9Hz, 1H), 8.25-8.12 (m, 1H), 7.35 (dd, J=J=7.8,4.7Hz,
1H), 5.76 (d, J=J=8.2Hz, 1H), 5.60 (d, J=J=9.4Hz, 1H), 4.77 (d, J=J=3.2Hz, 1H), 4.28
(qd, J=J=7.1,2.8Hz, 2H), 3.10 (t, J=J=2.9Hz, 1H), 2.38-2.12 (m, 1H), 1.80-1.73 (m,
1H), 1.73-1.64 (m, 1H), 1.58 (t, J=J=11.1Hz, 2H), 1.48-1.36 (m, 1H), 1.33-1.23 (m, 5H),
1.20-1.07 (m, 2H), 1.03 (s, 9H), 0.90-0.79 (m, 1H)；MS(ESI+)m/z 466(M+H)+。
Core 20D
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- picoline -3- base) -4- nitre
Base pyrrolidines -2- formic acid esters
Core 20C (238mg, 0.511mmol) is dissolved in dioxanes (5108 μ L), and adds PdCl2(dppf) ([1,1 '-
Bis- (diphenylphosphino) ferrocene] dichloro palladium (II), 18.69mg, 0.026mmol).Gained suspension nitrogen jet 15 is divided
Clock adds zinc methide (1.02mL, 1.022mmol) of the 1M in heptane later.Gained clarification pale yellow solution is heated to
85 DEG C are kept for 30 minutes.Mixture is cooled to room temperature, 5 DEG C of < are then cooled in ice bath, and by being slowly added saturation
Watersoluble chlorinated ammonium (1.0mL) quenching.Solvent is reduced under nitrogen flowing.Rough material is used into 24g silicagel column 5-100% acetic acid second
Ester/heptane gradient carries out purifying 20 minutes, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (hexamethylene carbonyl
Base) -5- (2- picoline -3- base) -4- nitro-pyrrole alkane -2- formic acid esters (165mg, 0.370mmol, 72.5% yield).1H
NMR (400MHz, DMSO-d6) δ ppm 8.30 (dd, J=J=4.8,1.7Hz, 1H), 8.12 (s, 1H), 7.10 (dd, J=J=
8.0,4.8Hz, 1H), 5.75-5.61 (m, 2H), 4.72 (d, J=J=3.5Hz, 1H), 4.27 (qd, J=J=7.1,1.6Hz,
2H), 3.09 (t, J=3.1Hz, 1H), 2.59 (s, 3H), 2.12 (s, 1H), 1.78-1.61 (m, 2H), 1.53 (s, 2H),
1.38-1.20 (m, 6H), 1.12 (q, J=11.2,10.1Hz, 1H), 1.03 (s, 9H), 0.91-0.78 (m, 2H)；MS(ESI+)
m/z 446(M+H)+。
Core 21
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 21A
(E)-ethyl 2- ((2- isopropoxy benzal) amino) acetic acid esters
To in methylene chloride (80mL) ethyl 2- amion acetic acid ester hydrochloride (CAS# 623-33-6) (4.68g,
33.5mmol) and in magnesium sulfate (4.03g, 33.5mmol) add triethylamine (4.67mL, 33.5mmol).By mixture in environment
At a temperature of stir 5 minutes, 2- isopropoxide benzaldehyde [CAS# 22921-58-0] (5g, 30.5mmol) then is added dropwise.It will mixing
Object is stirred overnight.Mixture is filtered and is washed with methylene chloride (10mL x 2).Combined organic layer is washed with brine, is passed through
MgSO4It is dried, filtered and concentrated to provide title compound, 7.28g (96% yield).1H NMR (501MHz, chloroform-d) δ ppm
8.74 (d, J=1.5Hz, 1H), 8.04 (dd, J=7.8,1.8Hz, 1H), 7.38 (ddd, J=8.4,7.3,1.8Hz, 1H),
7.00-6.95 (m, 1H), 6.95-6.91 (m, 1H), 4.66-4.60 (m, 1H), 4.42 (d, J=1.4Hz, 2H), 4.26 (q, J
=7.1Hz, 2H), 1.38 (d, J=6.1Hz, 6H), 1.32 (t, J=7.1Hz, 3H).
Core 21B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.109g, 0.144mmol) and copper trifluoromethanesulfcomposite
(I) the mixture N in dimer benzene complex (0.030g, 0.060mmol) tetrahydrofuran (40mL) cooling in ice bath2
Injection 1 hour.The core 21A (7g, 28.1mmol) in 10mL tetrahydrofuran is added, 2- methyl propyl- 2- potassium alcoholate is then added
(10.80mg, 0.096mmol), and (E) -3,3- dimethyl -1- nitro but-1-ene (1.632g, 12.64mmol) is added dropwise, it keeps
10 DEG C of internal temperature <.Mixture is stirred at the same temperature 2 hours, and watersoluble chlorinated with ethyl acetate (50mL) and saturation
Ammonium (50mL) dilution.Organic layer is saturated aqueous NaHCO3With salt water washing, and through Na2SO4It is dried, filtered and concentrated.?
Mark is provided via the purifying (ethyl acetate in heptane elutes under 0-40% gradient) that chromatography carries out on 80g silicagel column
Inscribe compound, 2.84g (62.4% yield).1H NMR (501MHz, chloroform-d) δ ppm 7.29-7.22 (m, 2H), 6.93 (td,
J=7.6,1.1Hz, 1H), 6.87 (dt, J=8.3,0.7Hz, 1H), 5.44 (dd, J=5.5,2.2Hz, 1H), 4.69 (dtd, J
=12.1,6.0,0.7Hz, 1H), 4.54 (s, 1H), 4.34 (qd, J=7.1,2.0Hz, 2H), 3.81 (s, 1H), 3.45 (s,
1H), 2.87 (dd, J=7.1,2.2Hz, 1H), 1.48 (d, J=6.0Hz, 3H), 1.41-1.34 (m, 6H), 1.09 (s, 9H)；
MS(ESI+)m/z 379.1(M+H)+。
Core 22
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 22A
(E)-ethyl 2- (benzylideneamino) acetic acid esters
At ambient temperature, by ethyl 2- amion acetic acid ester hydrochloride (30g, 215mmol) and magnesium sulfate (51.7g,
430mmol) the stirring in methylene chloride (358mL), and triethylamine (30.0mL, 215mmol) is added in suspension.It is stirring
It mixes after five minutes, is added dropwise benzaldehyde (21.78mL, 215mmol), and suspension is stirred at ambient temperature 16 hours.It will consolidate
Body material is removed by sinter funnel via filtering, and filter cake is washed with methylene chloride (15mL).By filtrate with 2x20mL's
Water washing is dried over sodium sulfate, and is filtered and is concentrated to provide title compound, it is used without other purifying.1H
NMR (501MHz, chloroform-d) δ ppm 8.29 (s, 1H), 7.78 (dd, J=7.9,1.7Hz, 2H), 7.47-7.36 (m, 3H),
4.39 (d, J=1.3Hz, 2H), 4.24 (q, J=7.1Hz, 2H), 1.30 (t, J=7.2Hz, 3H).
Core 22B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphines) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2- base)
Amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.261g, 0.347mmol) and copper trifluoromethanesulfcomposite (I)
Dimer benzene complex (0.076g, 0.151mmol), which is dissolved in, has used N2Stream sprays in 1 hour tetrahydrofuran (67.0mL).
Gained mixture is stirred 1 hour at ambient temperature, and is addedMolecular sieve (8g, 30.1mmol) then adds (E)-
Ethyl 2- ((2- benzylidene) amino) solution of acetic acid esters (8g, 36.2mmol) in 3mL tetrahydrofuran.Gained is hanged
Supernatant liquid is cooled to 5 DEG C of < in ice-water bath.Be added dropwise 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.241mL,
0.241mmol), then through 10 minutes addition (E) -3,3- dimethyl -1- nitro but-1-ene (3.89g, 30.1mmol) in 2mL
Solution in tetrahydrofuran keeps internal temperature to be lower than 6 DEG C.It is stirred in ice bath after twenty minutes, by reaction mixture first
Base tertbutyl ether (30mL) dilution is stirred 5 minutes together with aqueous ammonium chloride (20mL) is saturated, is then filtered by diatomite.
These layers are separated, and organic layer are washed with the aqueous ammonium chloride (2x10mL) of saturation, salt water (10mL), and dry through sodium sulphate
It is dry.After filtering, filtrate is concentrated in a vacuum to provide thick residue, by it via purified by flash chromatography, in 80g silicagel column
Upper 0: 100 to 60: 40 methyl tertiary butyl ether(MTBE)s: heptane elutes 25 minutes, to provide the title compound of 2.30g.1H NMR
(400MHz, chloroform-d) δ ppm 7.37-7.14 (m, 2H), 6.99-6.90 (m, 1H), 6.88 (dd, J=8.2,1.1Hz, 1H),
5.35 (ddd, J=5.8,2.5,0.9Hz, 1H), 4.56 (dd, J=13.0,5.7Hz, 1H), 4.40-4.22 (m, 2H), 3.90
(s, 3H), 3.81-3.72 (m, 1H), 3.37 (t, J=11.6Hz, 1H), 2.90 (ddd, J=7.3,2.5,0.9Hz, 1H),
1.39-1.30 (m, 3H), 1.07 (s, 9H)；MS(ESI+)m/z 351.1(M+H)+。
Core 23
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- fluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 23A
(E)-ethyl 2- ((2- fluorine benzal) amino) acetic acid esters
To ethyl 2- amion acetic acid ester hydrochloride (11.8g, 84.7mmol) and magnesium sulfate (11.7g, 96.7mmol) two
Triethylamine (12.5mL, 88.7mmol) is added in mixture in chloromethanes (100mL).It stirs the mixture for 20 minutes and is added dropwise
2- fluorobenzaldehyde (10.0g, 80.6mmol).Gained mixture is stirred at room temperature overnight.Solid is filtered out and uses dichloromethane
Alkane (200mL) washing.Filtrate water (100mL) and salt water (100mL) are washed, through MgSO4It is dried, filtered and concentrated to provide
Title compound (E)-ethyl 2- ((2- fluorine benzal) amino) acetic acid esters (16.0g, 76.6mmol, 95% yield).1H NMR
(400MHz, CDCl3) δ ppm 8.60 (s, 1H), 8.07-8.03 (m, 1H), 7.45-7.39 (m, 1H), 7.20-7.11 (m,
1H), 7.08-7.06 (m, 1H), 4.43 (s, 2H), 4.27,4.24 (dd, J=7.2Hz, 14.4Hz, 2H), 1.36-1.32 (m,
3H), 1.33-1.26 (m, 3H)；LC-MS(ESI+)m/z210(M+H)+。
Core 23B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- fluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Under an inert atmosphere, to equipped with activationIt is added in molecular sieve and the flame-dried Schlenk pipe of stirring rod
In the anhydrous tetrahydro furan (160mL) newly distilled copper trifluoromethanesulfcomposite (I) dimer benzene complex (417.8mg,
0.83mmol) and (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (1.45g, 1.93mmol).Stir the mixture for 15 points
Clock is simultaneously cooled to 0 DEG C.(E)-ethyl 2- ((2- fluorine benzal) amino) acetic acid esters (16.0g, 76.6mmol) is added, is then added
Potassium tert-butoxide (1.33mL, 1.33mmol) and (E) -3,3- dimethyl -1- nitro but-1-ene (8.56g, 66.36mmol).It will be anti-
It answers mixture to stir 2 hours at 0 DEG C, is then filtered by short silica gel plug.Filtrate is concentrated.Residue is passed through into silicagel column color
Spectrometry (elutes) purifying with 10% petrol ether/ethyl acetate, to provide title compound (13.55g, 40.09mmol, 58.6%
Yield, ee=95.3%).1H NMR (400MHz, CDCl3) δ ppm 7.33-7.30 (m, 2H), 7.17-7.15 (m, 1H), 7.07
(t, J=8.4Hz, 1H), 5.24-5.22 (m, 1H), 4.60 (t, J=6.0Hz, 1H), 4.35-4.29 (m, 2H), 3.80 (t, J
=3.6Hz, 1H), 3.33 (t, J=11.2Hz, 1H), 2.96-2.93 (m, 1H), 1.35 (t, J=7.2Hz, 3H), 1.06 (s,
9H)；LC-MS(ESI+)m/z 339(M+H)+。
Core 24
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 24A
(E)-ethyl 2- ((2- chlorine benzal) amino) acetic acid esters
By ethyl 2- amion acetic acid ester hydrochloride (1.85g, 13.25mmol) and magnesium sulfate (3.19g, 26.5mmol) two
Mixture in chloromethanes (22.09mL) is handled with triethylamine (1.847mL, 13.25mmol), stirring 30 minutes and with 2- chlorobenzene
Solution processing of the formaldehyde (1.863g, 13.25mmol) in 3mL methylene chloride.Reaction is stirred overnight at ambient temperature.It will
Filtrate is concentrated solid material filtration, adds toluene (5mL), and mixture is filtered again.Filtrate is concentrated to provide (E)-
Ethyl 2- ((2- chlorine benzal) amino) acetic acid esters (2.76g, 12.23mmol, 92% yield).1H NMR (400MHz, chloroform-
D) δ ppm 8.77 (d, J=1.5Hz, 1H), 8.19-8.04 (m, 1H), 7.45-7.39 (m, 2H), 7.34 (ddd, J=8.3,
6.0,2.6Hz, 1H), 4.48 (d, J=1.5Hz, 2H), 4.28 (q, J=7.2Hz, 2H), 1.34 (t, J=7.1Hz, 3H).
Core 24B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.175g, 0.232mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.047g, 0.093mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 1 hour
In (19.36mL).Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature, and adds (E)-ethyl 2-
((the 2- chlorine benzal) amino) solution of acetic acid esters (2.75g, 12.19mmol) in 2mL tetrahydrofuran.By acquired solution in ice
5 DEG C of < are cooled in water-bath.Be added dropwise in tetrahydrofuran 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.209mL,
0.209mmol), pure (E) -3,3- dimethyl -1- nitro but-1-ene (1.5g, 11.61mmol) then was added through 20 minutes,
Temperature is kept to be lower than 7 DEG C.Reaction mixture is stirred 1 hour at 0 DEG C.Mixture 60mL is saturated aqueous ammonium chloride to quench.
Mixture is simultaneously warmed to environment temperature by addition ethyl acetate (100mL).Organic layer is separated, with the aqueous ammonium chloride of saturation and salt
Water washing twice, and is filtered by silicagel pad.Filtrate is concentrated.It adds heptane (70mL), and filtering precipitate (2.5g).It will filter
Liquid is purified by using the chromatography of 12g silicagel column, with 0-60% heptane/ethyl acetate gradient elution 20 minutes, with
Offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters (2.85g,
8.03mmol, 69.2% yield).1H NMR (400MHz, DMSO-d6) δ ppm 7.56-7.48 (m, 1H), 7.45-7.38 (m,
1H), 7.35-7.24 (m, 2H), 5.25 (dd, J=6.7,3.0Hz, 1H), 4.71 (t, J=7.0Hz, 1H), 4.19 (qq, J=
7.3,3.7Hz, 2H), 3.78 (t, J=7.3Hz, 1H), 3.68 (t, J=7.3Hz, 1H), 3.07 (dd, J=7.4,3.0Hz,
1H), 1.24 (t, J=7.1Hz, 3H), 0.94 (s, 9H), 0.96 (s, 9H)；MS(APCI+)m/z 355(M+H+).
Core 25
(2S, 3R, 4S, 5S)-ethyl 5- (2- bromophenyl) -3- (tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 25A
(E)-ethyl 2- ((2- bromine benzal) amino) acetic acid esters
At ambient temperature, by ethyl 2- amion acetic acid ester hydrochloride (2.63g, 18.85mmol) and magnesium sulfate
(2.269g, 18.85mmol) stirring in methylene chloride (28.6mL), and add triethylamine (2.63mL, 18.85mmol).It will
Mixture stirs 5 minutes, is added dropwise 2- bromobenzaldehyde (2.0mL, 17.13mmol), and mixture is stirred 16 at ambient temperature
Hour.Solid material is passed through into disposable plastic frit and is washed with methylene chloride.By organic layer 30mL water washing,
Then be dried over sodium sulfate, filter and be concentrated with offer (E)-ethyl 2- ((2- bromine benzal) amino) acetic acid esters (4.6g,
17.03mmol, 99% yield).1H NMR (400MHz, CDCl3) δ ppm 8.70 (d, J=1.6Hz, 1H), 8.12 (dd, J=
7.7,1.9Hz, 1H), 7.60 (dd, J=7.8,1.3Hz, 1H), 7.38 (tt, J=7.6,1.1Hz, 1H), 7.35-7.27 (m,
1H), 4.48 (d, J=1.4Hz, 2H), 4.28 (q, J=7.1Hz, 2H), 1.34 (t, J=7.1Hz, 3H)；MS(ESI+)m/z
270(M+H)+。
Core 25B
(2S, 3R, 4S, 5S)-ethyl 5- (2- bromophenyl) -3- (tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.147g, 0.195mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.042g, 0.084mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 1 hour
In (34.3mL).Gained mixture is stirred 1.5 hours at ambient temperature, and is added after being cooled to 5 DEG C of < in ice-water bath
(E)-ethyl 2- ((2- bromine benzal) amino) acetic acid esters (4.63g, 17.14mmol).2- methyl propyl- 2- potassium alcoholate is added dropwise, and (1M exists
In tetrahydrofuran, 0.134mL, 0.134mmol), then through 25 minutes pure (E) -3,3- dimethyl -1- nitro butyl- 1- of addition
Alkene (2.324g, 18.00mmol) is kept for 10 DEG C of internal temperature <.After addition is completed and stirs reaction 90 minutes, LC-MS
It shows complete conversion.Mixture is diluted with methyl tertiary butyl ether(MTBE) (150mL), and is saturated aqueous chlorine with 50mL at ambient temperature
Change ammonium to stir together 15 minutes.These layers are separated, and by organic layer saturated sodium bicarbonate aqueous solution and salt water washing.To have
Machine layer is dried over sodium sulfate, and is filtered and is concentrated to provide thick solid, which is settled out from 50mL heptane.Mixture is existed
Be cooled to 5 DEG C of < in ice bath and continue 15 minutes, and resulting material is filtered to and used 20mL heptane wash, with offer (2S, 3R, 4S,
5S)-ethyl 5- (2- bromophenyl) -3- (tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters (4.303g, 10.78mmol, 62.9%
Yield).1H NMR (400MHz, CDCl3) δ ppm 7.58 (dd, J=8.0,1.2Hz, 1H), 7.41-7.29 (m, 2H), 7.24-
7.14 (m, 1H), 5.43 (dd, J=5.9,2.3Hz, 1H), 4.70 (dd, J=10.7,5.9Hz, 1H), 4.33 (qd, J=7.1,
1.2Hz, 2H), 3.82 (t, J=7.5Hz, 1H), 3.22 (t, J=9.8Hz, 1H), 3.03 (dd, J=7.0,2.3Hz, 1H),
1.36 (t, J=7.1Hz, 3H), 1.08 (s, 9H)；MS(APCI+)m/z 399(M+H)+。
Core 26
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (2- (trifluoromethyl) phenyl) pyrrolidines -2- formic acid
Ester
Core 26A
(E)-ethyl 2- ((2- (trifluoromethyl) benzal) amino) acetic acid esters
By ethyl 2- amion acetic acid ester hydrochloride (6.01g, 43.1mmol) and magnesium sulfate (5.88g, 48.8mmol) two
Slurries in chloromethanes (100mL) stir at 0 DEG C.Triethylamine (6.00mL, 43.1mmol) is added dropwise and by mixture in room temperature
Lower stirring 1 hour.Add 2- (trifluoromethyl) benzaldehyde (5g, 28.7mmol).After 15 hours, solid is filtered and uses dichloromethane
Alkane (3x200mL) washing.Dichloromethane layer is washed with water (2x100mL), dry (Na2SO4), it filters and is concentrated, to provide
(E)-ethyl 2- ((2- (trifluoromethyl) benzal) amino) acetic acid esters (7.2g, 25.8mmol, 90% yield).1H NMR
(400MHz, CDCl3) δ ppm 8.64 (s, 1H), 8.28 (d, J=7.6Hz, 1H), 7.61-7.51 (m, 2H), 7.69-7.67
(m, 1H), 4.45 (s, 2H), 4.24 (q, J=6.8Hz, 2H), 1.30 (t, J=7.0Hz, 3H).
Core 26B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- (2- (trifluoromethyl) phenyl) pyrrolidines -2- formic acid
Ester
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.169g, 0.225mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.048g, 0.095mmol) is added under an argon containing activationMolecular sieve and stirring rod
Flame-dried flask in.Add the anhydrous tetrahydro furan (20mL) newly distilled.After stirring 15 minutes, solution is cooled to 0
DEG C, (E)-ethyl 2- ((2- (trifluoromethyl) benzal) amino) acetic acid esters (2.408g, 9.29mmol) is added later, is then added
Add potassium tert-butoxide (0.155mL, 0.155mmol).Be slowly added (E) -3,3- dimethyl -1- nitro but-1-ene (1g,
7.74mmol).Reaction mixture is stirred 5 hours at 0 DEG C, and adds water (80mL) into flask.By aqueous layer with ethyl acetate
(2x100mL) extraction.Organic layer is merged, is washed with salt water (2x80mL), through Na2SO4It is dried, filtered and concentrated.By rough material
By silica gel chromatography (ethyl acetate/petroleum mixture, 1: 40) purify, with provide title compound (2g, 5.10mmol,
65.8% yield).1H NMR (400MHz, CDCl3) δ ppm 7.69-7.41 (m, 4H), 5.07-5.06 (m, 1H), 4.81-478
(m, 1H), 4.32 (q, 2H), 3.82 (t, J=7.2Hz, 1H), 3.15-3.13 (m, 1H), 3.01 (t, J=8.6Hz, 1H),
1.34 (t, J=7.2Hz, 3H), 1.03 (s, 9H).
Core 27
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoromethyl) phenyl) -4- nitro-pyrrole alkane -2- formic acid
Ester
Core 27A
(E)-ethyl 2- ((2- (difluoromethyl) benzal) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (1.788g, 12.81mmol) and magnesium sulfate (3.08g, 25.6mmol) are existed
Mixture in methylene chloride (21.35mL) (anhydrous) is handled with triethylamine (1.785mL, 12.81mmol), is stirred 10 minutes,
And it is handled with solution of 2- (difluoromethyl) benzaldehyde (2.00g, 12.81mmol) in 4mL methylene chloride.By mixture in ring
It is stirred overnight at a temperature of border.By solid material filtration, filtrate is concentrated, is added toluene (25mL), and mixture is filtered again.
By mixture be concentrated with provide (E)-ethyl 2- ((2- (difluoromethyl) benzal) amino) acetic acid esters (3.0g, 12.44mmol,
97% yield), it is directly used in next step.1H NMR (400MHz, CDCl3) δ ppm 8.59 (t, J=1.4Hz, 1H),
8.00-7.87 (m, 1H), 7.70 (dd, J=6.6,2.3Hz, 1H), 7.63-7.52 (m, 2H), 7.35 (t, J=55.1Hz,
1H), 4.47 (d, J=1.3Hz, 2H), 4.28 (q, J=7.1Hz, 2H), 1.34 (t, J=7.1Hz, 3H).
Core 27B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoromethyl) phenyl) -4- nitro-pyrrole alkane -2- formic acid
Ester
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.187g, 0.249mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.050g, 0.099mmol), which is dissolved in, has used N2Stream sprays 1 hour tetrahydrofuran (12.9mL)
In.Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature, and adds (E)-ethyl 2- ((2- (difluoro
Methyl) benzal) amino) solution of the acetic acid esters (3.0g, 12.44mmol) in 1.5mL tetrahydrofuran.By acquired solution in ice
5 DEG C of < are cooled in water-bath.The 2- methyl propyl- 2- potassium alcoholate (0.224mL, 0.224mmol) in tetrahydrofuran is added dropwise, then passes through
2 minutes pure (E) -3,3- dimethyl -1- nitro but-1-enes (1.606g, 12.44mmol) of addition, keep internal temperature to be lower than 7
℃.Reaction mixture is stirred 3 hours at 0 DEG C.Mixture 10mL is saturated aqueous ammonium chloride quenching addition 30mL acetic acid second
Ester, and it is warmed to environment temperature.Organic layer is separated and uses the aqueous ammonium chloride (2x20mL) of saturation and salt water washing, and is led to
Cross silicagel pad filtering.Filtrate is concentrated.Residue is ground with heptane, is decanted, is settled out from hot heptane, and is filtered to provide
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoromethyl) phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
(2.48g, 6.70mmol, 53.8% yield).1H NMR (400MHz, DMSO-d6) δ ppm 7.64 (d, J=7.7Hz, 1H),
7.57-7.53 (m, 1H), 7.48 (t, J=7.4Hz, 1H), 7.45-7.39 (m, 1H), 7.38 (t, J=54.4Hz, 1H), 5.19
(dd, J=7.0,3.4Hz, 1H), 4.79 (t, J=6.5Hz, 1H), 4.19 (qd, J=7.1,2.4Hz, 2H), 3.83-3.61
(m, 2H), 3.11 (dd, J=6.9,3.5Hz, 1H), 1.24 (t, J=7.1Hz, 3H), 0.93 (s, 9H)；MS(ESI+)m/z
371(M+H)+。
Core 28
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- ethylphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 28A
(E)-ethyl 2- ((2- ethylbenzylidene) amino) acetic acid esters
By ethyl 2- amion acetic acid ester hydrochloride (1.85g, 13.25mmol) and magnesium sulfate (3.19g, 26.5mmol) two
Mixture in chloromethanes (22mL) is handled with triethylamine (1.847mL, 13.25mmol), stirring 10 minutes and with 2- ethylo benzene
Solution processing of the formaldehyde (1.778g, 13.25mmol) in 1mL methylene chloride.Reaction is stirred overnight at ambient temperature.It will
Solid material filtration washs filtrate water, and organic fraction is separated.By organic fraction Na2SO4It is dried, filtered and concentrated
With offer (E)-ethyl 2- ((2- ethylbenzylidene) amino) acetic acid esters (2.65g, 12.09mmol, 91% yield).1H NMR
(400MHz, chloroform-d) δ ppm 8.63 (s, 1H), 7.96 (dd, J=7.8,1.5Hz, 1H), 7.37 (td, J=7.5,1.5Hz,
1H), 7.26 (d, J=6.1Hz, 1H), 7.25-7.19 (m, 1H), 4.43 (d, J=1.4Hz, 2H), 4.26 (q, J=7.1Hz,
2H), 2.89 (q, J=7.5Hz, 2H), 1.32 (t, J=7.1Hz, 3H), 1.26 (t, J=7.6Hz, 3H).
Core 28B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- ethylphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.182g, 0.242mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.049g, 0.097mmol) is dissolved in the tetrahydrofuran (18mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature, and is added in 1mL tetrahydrofuran
(E)-ethyl 2- ((2- ethylbenzylidene) amino) acetic acid esters (core 28A, 2.65g, 12.09mmol), and by acquired solution in ice
5 DEG C of < are cooled in water-bath.The 2- methyl propyl- 2- potassium alcoholate (0.218mL, 0.218mmol) in tetrahydrofuran is added dropwise, then passes through
(E) -3,3- dimethyl -1- nitro but-1-ene (1.561g, 12.09mmol) of the addition in 2 minutes in 1mL tetrahydrofuran, keeps
Internal temperature is lower than 7 DEG C.Reaction mixture is stirred 1.5 hours at 0 DEG C.By mixture 20mL be saturated aqueous ammonium chloride and
The quenching of 50mL ethyl acetate, and it is warmed to environment temperature.Organic layer is separated, is washed twice with aqueous ammonium chloride washed is saturated, then
It is washed with brine, and is filtered by silicagel pad.Filtrate is concentrated, and is purified by using the chromatography of 40g silicagel column, is used
0-60% heptane/ethyl acetate gradient elution 20 minutes.Rough material is ground with heptane, and sediment is filtered to provide
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- ethylphenyl) -4- nitro-pyrrole alkane -2- formic acid esters (2.11g,
6.06mmol, 50.1% yield).1H NMR (501MHz, DMSO-d6) δ ppm 7.40-7.29 (m, 1H), 7.25-7.15 (m,
2H), 7.11 (td, J=7.4,1.8Hz, 1H), 5.17 (dd, J=7.0,3.5Hz, 1H), 4.64 (t, J=7.4Hz, 1H),
4.19 (qd, J=7.1,3.8Hz, 2H), 3.72 (t, J=7.6Hz, 1H), 3.47 (t, J=7.5Hz, 1H), 3.07 (dd, J=
7.9,3.5Hz, 1H), 2.72 (dt, J=15.0,7.5Hz, 1H), 2.63 (dt, J=15.0,7.5Hz, 1H), 1.22 (dt, J=
16.4,7.3Hz, 6H), 0.93 (s, 9H)；MS(APCI+)m/z 349(M+H+).
Core 29
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (3- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 29A
(E)-ethyl 2- ((3- chlorine benzal) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (5.96g, 42.7mmol) and magnesium sulfate (5.14g, 42.7mmol) are suspended
In methylene chloride (50.8mL).It adds triethylamine (5.95mL, 42.7mmol), and reaction mixture is stirred at ambient temperature
It mixes 1 hour, adds 3- chlorobenzaldehyde (4.03mL, 35.6mmol) via syringe later.By reaction mixture in environment temperature
Under be stirred overnight.Solid is removed using sinter funnel via filtering, and filter cake is washed with methylene chloride (10mL).By filtrate
It with 10mL water and 10mL salt water quick wash, and is dried over sodium sulfate, filters and be simultaneously concentrated in a vacuum, to provide title compound
Object uses it without other purifying.1H NMR (400MHz, CDCl3) δ ppm 8.24 (d, J=1.3Hz, 1H), 7.81
(t, J=1.8Hz, 1H), 7.62 (dt, J=7.6,1.4Hz, 1H), 7.48-7.29 (m, 2H), 4.40 (d, J=1.3Hz, 2H),
4.24 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H).
Core 29B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (3- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.192g, 0.255mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.056g, 0.111mmol), which is dissolved in, has used N2Stream sprays in 1 hour tetrahydrofuran (50mL).
Acquired solution is stirred 1 hour at ambient temperature, and addedMolecular sieve (6g, 22.16mmol) then adds (E)-second
Base 2- ((the 3- chlorine benzal) amino) solution of acetic acid esters (6.0g, 26.6mmol) in 3mL tetrahydrofuran.By gained suspension
5 DEG C of < are cooled in ice-water bath.2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.177mL, 0.177mmol) is added dropwise,
Then through 10 minutes addition (E) -3,3- dimethyl -1- nitro but-1-ene (2.86g, 22.16mmol) in 2mL tetrahydrofuran
Solution, keep temperature be lower than 10 DEG C.At the same temperature after ten minutes, as measured by LC-MS, reaction is completed.It will be anti-
It is saturated aqueous ammonium chloride quenching using 5mL, and is filtered after with methyl tertiary butyl ether(MTBE) (50mL) dilution by diatomite.By filtrate
It is stirred 15 minutes with the aqueous ammonium chloride (20mL) of saturation at ambient temperature, and these layers is separated.By organic layer saturated water
Property ammonium chloride and salt water washing, be dried over sodium sulfate, filter and be simultaneously concentrated in a vacuum to provide thick residue.Rough material is loaded
Onto 120g silicagel column, and with 0: 100 to 30: 70 methyl tertiary butyl ether(MTBE)s: heptane elutes 20 minutes, titled to provide 5.83g
Close object.1H NMR (501MHz, CDCl3) δ ppm 7.33 (dq, J=1.7,1.0Hz, 1H), 7.30-7.24 (m, 2H), 7.22-
7.16 (m, 1H), 5.11 (dd, J=6.0,2.5Hz, 1H), 4.40 (dd, J=12.0,6.0Hz, 1H), 4.31 (qd, J=7.1,
1.1Hz, 2H), 3.79 (dd, J=9.6,7.1Hz, 1H), 3.21 (dd, J=11.9,9.7Hz, 1H), 2.96 (dd, J=7.2,
2.6Hz, 1H), 1.34 (t, J=7.1Hz, 3H), 1.05 (s, 9H)；MS(ESI+)m/z 355.1(M+H)+。
Core 30
(2S, 3R, 4S, 5S)-ethyl 5- (3- bromophenyl) -3- (tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 30A
(E)-ethyl 2- ((3- bromine benzal) amino) acetic acid esters
At ambient temperature, by ethyl 2- amion acetic acid ester hydrochloride (2.490g, 17.84mmol) and magnesium sulfate
(2.147g, 17.84mmol) stirring in methylene chloride (24.13mL), and add triethylamine (2.486mL, 17.84mmol).
It stirs the mixture for 5 minutes, and 3- bromobenzaldehyde (1.890mL, 16.21mmol) is added dropwise.Mixture is stirred at ambient temperature
It mixes 16 hours.Solid material is passed through into disposable plastic frit and is washed with methylene chloride.By organic layer 30mL water
Washing, be dried over sodium sulfate, filter and be concentrated with offer (E)-ethyl 2- ((3- bromine benzal) amino) acetic acid esters (4.38g,
16.21mmol, 100% yield).1H NMR (500MHz, CDCl3) δ ppm 8.27 (d, J=1.4Hz, 1H), 8.01 (t, J=
1.8Hz, 1H), 7.70 (dt, J=7.7,1.3Hz, 1H), 7.61 (ddd, J=8.0,2.0,1.0Hz, 1H), 7.33 (t, J=
7.8Hz, 1H), 4.44 (d, J=1.3Hz, 2H), 4.28 (q, J=7.1Hz, 2H), 1.35 (t, J=7.1Hz, 3H)；MS(ESI
+)m/z 224(M+H)+。
Core 30B
(2S, 3R, 4S, 5S)-ethyl 5- (3- bromophenyl) -3- (tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.139g, 0.184mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.040g, 0.079mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 1 hour
In (32.4mL).Gained mixture is stirred 1.5 hours at ambient temperature, and is added after being cooled to 5 DEG C of < in ice-water bath
(E)-ethyl 2- ((3- bromine benzal) amino) acetic acid esters (4.38g, 16.21mmol).2- methyl propyl- 2- potassium alcoholate is added dropwise, and (1M exists
In tetrahydrofuran, 0.127mL, 0.127mmol), then through 25 minutes pure (E) -3,3- dimethyl -1- nitro butyl- 1- of addition
Alkene (2.199g, 17.03mmol) is kept for 10 DEG C of internal temperature <.After the completion of addition, stir the mixture for 2 hours.2- is added again
Methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.127mL, 0.127mmol).After 30 minutes, by reaction mixture methyl- tert
Butyl ether (150mL) dilution, and stirred 15 minutes together with the aqueous ammonium chloride of 50mL saturation at ambient temperature.By these layers point
From.It by organic layer saturation aqueous sodium bicarbonate and salt water washing, is dried over sodium sulfate, filters and be concentrated and is thick remaining to provide
Object grinds the thick residue heptane of 3x5mL.By heptane insolubles using 80g silicagel column with 5%-50% ethyl acetate/
Heptane carries out chromatography 40 minutes, with offer (2S, 3R, 4S, 5S)-ethyl 5- (3- bromophenyl) -3- (tert-butyl) -4- nitro-pyrrole
Alkane -2- formic acid esters (2.76g, 6.91mmol, 42.6% yield).N-hexane (about 1mL) is added in about 50mg residue, and
Mixture is warmed to 45 DEG C, is then allowed to cool.1H NMR (501MHz, CDCl3) δ ppm 7.50 (d, J=1.9Hz, 1H),
7.45 (dt, J=7.5,1.7Hz, 1H), 7.29-7.19 (m, 2H), 5.13 (dd, J=6.0,2.6Hz, 1H), 4.41 (dd, J=
11.9,6.0Hz, 1H), 4.33 (qd, J=7.1,1.1Hz, 2H), 3.81 (dd, J=9.5,7.2Hz, 1H), 3.27-3.17 (m,
1H), 2.98 (dd, J=7.2,2.5Hz, 1H), 1.37 (t, J=7.2Hz, 3H), 1.07 (s, 9H)；MS(APCI+)m/z 399
(M+H)+.Opposite and absolute stereochemistry is confirmed by X-ray analysis.
Core 31
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (3- (tert-butyl) phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 31A
(E)-ethyl 2- ((3- (tert-butyl) benzal) amino) acetic acid esters
To in CH2Cl2Ethyl 2- amion acetic acid ester hydrochloride (CAS#623-33-6,776mg, 5.56mmol) in (10mL)
Triethylamine (0.775mL, 5.56mmol) is added in magnesium sulfate (669mg, 5.56mmol).Mixture is stirred at ambient temperature
It mixes 5 minutes, 3- (tert-butyl) benzaldehyde (820mg, 5.05mmol) is added dropwise, and the mixture was stirred overnight.Mixture is filtered
And by solid CH2Cl2(10mL x 2) washing.By combined organic matter water and salt water washing, through MgSO4It dries, filters simultaneously
Concentration is to provide (E)-ethyl 2- ((3- (tert-butyl) benzal) amino) acetic acid esters (1.08g, 86% yield).1H NMR
(400MHz, CDCl3) δ ppm 8.31 (s, 1H), 7.81 (t, J=1.9Hz, 1H), 7.60 (dt, J=7.5,1.4Hz, 1H),
7.50 (ddd, J=7.8,2.1,1.2Hz, 1H), 7.37 (t, J=7.7Hz, 1H), 4.41 (d, J=1.2Hz, 2H), 4.25 (q,
J=7.1Hz, 2H), 1.36 (s, 9H), 1.32 (t, J=7.1Hz, 3H).
Core 31B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (3- (tert-butyl) phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (37mg, 0.049mmol) and copper trifluoromethanesulfcomposite (I)
Mixture of the dimer benzene complex (CAS#42152-46-5,10.18mg, 0.020mmol) in tetrahydrofuran (10mL) is used
N2Injection one hour.At 0 DEG C, the core 31A (1g, 4.04mmol) in tetrahydrofuran (5mL) is added, 2- methyl is then added dropwise
Propan-2-ol potassium (3.63mg, 0.032mmol), finally add (E) -3,3- dimethyl -1- nitro but-1-ene (548mg,
4.25mmol), 10 DEG C of internal temperature < are kept.Mixture is stirred at the same temperature one hour, with ethyl acetate (20mL)
It dilutes with aqueous ammonium chloride (20mL) is saturated, and stirs 30 minutes at ambient temperature.By organic layer NaHCO3It is washed with salt
It washs, through Na2SO4It is dried, filtered and concentrated to provide title compound, it is used in next step without further purification.
LC/MS(APCI+)m/z 377(M+1)+。
Core 32
(2S, 3R, 4S, 5R)-ethyl 3- (tert-butyl) -5- (1- isopropyl -1H- pyrazoles -5- base) -4- nitro-pyrrole alkane -
2- formic acid esters
Core 32A
(E)-ethyl 2- (((1- isopropyl -1H- pyrazoles -5- base) methylene) amino) acetic acid esters
At ambient temperature, by ethyl 2- amion acetic acid ester hydrochloride (2.223g, 15.92mmol) and magnesium sulfate
(1.917g, 15.92mmol) stirring in methylene chloride (24.13mL), and add triethylamine (2.185mL, 15.67mmol).
It stirs the mixture for 5 minutes, and 1- isopropyl -1H- pyrazoles -5- formaldehyde (2.0g, 14.48mmol) is added dropwise.By mixture in ring
It is stirred 16 hours at a temperature of border.Solid material is passed through into disposable plastic frit and is washed with methylene chloride.It will be organic
Layer 30mL water washing, is dried over sodium sulfate, filters and be concentrated with offer (E)-ethyl 2- (((1- isopropyl -1H- pyrazoles -5-
Base) methylene) amino) acetic acid esters (3.23g, 14.47mmol, 100% yield).1H NMR (400MHz, CDCl3)δppm 8.29
(t, J=1.3Hz, 1H), 7.52 (d, J=1.9Hz, 1H), 6.58 (d, J=2.0Hz, 1H), 5.48 (p, J=6.6Hz, 1H),
4.38 (d, J=1.3Hz, 2H), 4.24 (q, J=7.2Hz, 2H), 1.50 (d, J=6.6Hz, 6H), 1.31 (t, J=7.1Hz,
3H)；MS(ESI+)m/z 224(M+H)+。
Core 32B
(2S, 3R, 4S, 5R)-ethyl 3- (tert-butyl) -5- (1- isopropyl -1H- pyrazoles -5- base) -4- nitro-pyrrole alkane -
2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.124g, 0.164mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.036g, 0.071mmol) is dissolved in the tetrahydrofuran sprayed with nitrogen stream 1 hour
In (28.9mL).Gained mixture is stirred 1.5 hours at ambient temperature, and is added after being cooled to 5 DEG C of < in ice-water bath
(E)-ethyl 2- (((1- isopropyl -1H- pyrazoles -5- base) methylene) amino) acetic acid esters (3.23g, 14.47mmol).2- is added dropwise
Methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.113mL, 0.113mmol), then through addition pure (E) -3,3- in 25 minutes
Dimethyl -1- nitro but-1-ene (1.962g, 15.19mmol) is kept for 10 DEG C of internal temperature <.After the completion of addition, reaction is stirred
It mixes 2 hours.Mixture is diluted with methyl tertiary butyl ether(MTBE) (150mL), and is saturated aqueous ammonium chloride with 50mL at ambient temperature
It stirs 15 minutes together.These layers are separated, and by organic layer with saturation aqueous sodium bicarbonate and salt water washing and through sodium sulphate
It is dry.After filtering, combined organic layer is concentrated and the heptane of 3x5mL is used to grind, and is stood overnight in dry ice in heptane.
Solvent is removed and resulting material is concentrated.N-hexane is added, mixture is ground and is stirred one hour at ambient temperature.It will
Mixture is filtered to provide solid, by solid 10mL heptane wash, with offer (2S, 3R, 4S, 5R)-ethyl 3- (tertiary fourth
Base) -5- (1- isopropyl -1H- pyrazoles -5- base) -4- nitro-pyrrole alkane -2- formic acid esters (2.556g, 7.25mmol, 50.1%
Rate).1H NMR (500MHz, CDCl3) δ ppm 7.50 (d, J=1.9Hz, 1H), 6.21 (d, J=1.9Hz, 1H), 5.04 (dd, J
=5.9,2.3Hz, 1H), 4.47 (ddd, J=21.6,12.9,6.2Hz, 2H), 4.35 (qd, J=7.2,1.8Hz, 2H), 3.82
(dd, J=9.4,6.6Hz, 1H), 3.30 (dd, J=12.3,9.5Hz, 1H), 3.02 (dd, J=6.7,2.3Hz, 1H), 1.60
(d, J=6.6Hz, 3H), 1.56 (d, J=6.5Hz, 3H), 1.37 (t, J=7.1Hz, 3H), 1.10 (s, 9H)；MS(APCI+)
m/z 353(M+H)+.Absolute chemical is confirmed by X-ray diffraction analysis.
Core 33
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (4- fluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 33A
(E)-ethyl 2- ((4- fluorine benzal) amino) acetic acid esters
To ethyl 2- amion acetic acid ester hydrochloride (33.7g, 242mmol) and magnesium sulfate (33.0g, 274mmol) in dichloro
Triethylamine (33.7mL, 242mmol) is added in mixture in methane (320mL).Mixture is stirred at room temperature 20 minutes
And 4- fluorobenzaldehyde (20.00g, 161mmol) is added dropwise.Gained mixture is stirred 20 hours at 25 DEG C.LC/MS shows to have reacted
At.Solid is filtered out and is washed with methylene chloride (200mL).Combined filtrate water (150mL) and salt water (150mL) are washed
It washs, through Na2SO4Be dried, filtered and concentrated with offer (E)-ethyl 2- ((4- fluorine benzal) amino) acetic acid esters (30g,
129mmol, 80% yield).1H NMR (400MHz, CDCl3) δ ppm 8.20 (s, 1H), 7.70-7.72 (m, 2H), 7.01-
7.05 (m, 2H), 4.31 (s, 2H), 4.16 (q, J=8Hz, 2H), 1.23 (t, J=8Hz, 3H)；LC/MS(ESI+)m/z
210.1(M+H)+。
Core 33B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (4- fluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Under an argon atmosphere, to containing activationIt is added in molecular sieve and the flame-dried Schlenk pipe of stirring rod
In the anhydrous tetrahydro furan (50mL) newly distilled copper trifluoromethanesulfcomposite (I) dimer benzene complex (145.1mg,
0.28mmol) and (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.423g, 0.561mmol).By mixture in room temperature
Lower stirring is subsequently cooled to 0 DEG C in 15 minutes.(E)-ethyl 2- ((4- fluorine benzal) amino) acetic acid esters is added into mixture
(4.86g, 23.23mmol), potassium tert-butoxide (0.387mL, 0.387mmol) and (E) -3,3- dimethyl -1- nitro but-1-ene
(2.50g, 19.36mmol).Mixture is stirred 6 hours at 0 DEG C.Solid is filtered by short silica gel plug.Filtrate is concentrated.
By residue by silica gel column chromatography (with 10% petrol ether/ethyl acetate elute) purify, with provide title compound (2S,
3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (4- fluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters (3.0g, 8.87mmol,
45.8% yield).1H NMR (400MHz, CDCl3) δ ppm 7.28-7.33 (m, 2H), 7.05-7.07 (m, 2H), 5.11 (dd, J
=4Hz, 8Hz, 1H), 4.44 (d, J=8Hz, 1H), 4.33 (q, J=8Hz, 2H), 3.82 (d, J=8Hz, 1H), 2.99 (dd, J
=4Hz, 8Hz, 1H), 1.36 (t, J=8Hz, 3H), 1.06 (s, 9H)；LC/MS(ESI+)m/z 339.2(M+H)+。
Core 34
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2,6- difluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 34A
(E)-ethyl 2- ((2,6- difluorobenzyliden) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (1.85g, 13.25mmol) and magnesium sulfate (3.19g, 26.5mmol) are existed
CH2Cl2Mixture in (22.09mL) (anhydrous) is handled with triethylamine (1.847mL, 13.25mmol), and stirring is used in combination for 10 minutes
2,6- difluorobenzaldehydes (1.883g, 13.25mmol) are in CH2Cl2Solution processing in (about 3mL).Bottle is covered and in room temperature
Under be stirred overnight.It is concentrated by solid material filtration, and by filtrate.Addition toluene (5mL) simultaneously filters mixture again.By filtrate
Concentration, will to provide (E)-ethyl 2- ((2,6- difluorobenzyliden) amino) acetic acid esters (2.9g, 12.76mmol, 96% yield)
It is directly used in next step.1H NMR (400MHz, chloroform-d) δ ppm 8.54 (d, J=1.3Hz, 1H), 7.13-6.81
(m, 3H), 4.49 (s, 2H), 4.28 (q, J=7.1Hz, 2H), 1.34 (t, J=7.1Hz, 3H).
Core 34B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2,6- difluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.175g, 0.232mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.047g, 0.093mmol) is dissolved in the tetrahydrofuran (19mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature.Add (E)-in 2mL tetrahydrofuran
Ethyl 2- ((2,6- difluorobenzyliden) amino) acetic acid esters (2.9g, 12.76mmol), and acquired solution is cooling in ice-water bath
To 5 DEG C of <.The 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.244mL, 0.244mmol) in tetrahydrofuran is added dropwise,
Then (E) -3,3- dimethyl -1- nitro but-1-ene (1.5g, 11.61mmol) through addition in 2 minutes in 2mL tetrahydrofuran,
Temperature is kept to be lower than 7 DEG C.Reaction mixture is stirred 1.5 hours at 0 DEG C.By mixture 20mL be saturated aqueous ammonium chloride and
The quenching of 50mL ethyl acetate, and it is warmed to environment temperature.Organic layer is separated, with the aqueous ammonium chloride of saturation and salt water washing two
It is secondary, and filtered by silicagel pad.Filtrate is concentrated.It adds heptane (60mL), sediment (1.5g) is filtered, and filtrate is passed through
It is purified using the chromatography of 40g silicagel column, it is thick to provide with 0-60% heptane/ethyl acetate gradient elution 20 minutes
Residue.Rough material is ground with heptane, and sediment is filtered to provide (2S, 3R, 4S, 5S)-ethyl 3- of comprehensive yield
(tert-butyl) -5- (2- ethylphenyl) -4- nitro-pyrrole alkane -2- formic acid esters (1.9g, 5.33mmol, 45.9% yield).1H
NMR (400MHz, DMSO-d6) δ ppm 7.64 (d, J=7.7Hz, 1H), 7.57-7.53 (m, 1H), 7.48 (t, J=7.4Hz,
1H), 7.45-7.39 (m, 1H), 7.38 (t, J=54.4Hz, 1H), 5.19 (dd, J=7.0,3.4Hz, 1H), 4.79 (t, J=
6.5Hz, 1H), 4.19 (qd, J=7.1,2.4Hz, 2H), 3.83-3.61 (m, 2H), 3.11 (dd, J=6.9,3.5Hz, 1H),
1.24 (t, J=7.1Hz, 3H), 0.93 (s, 9H)；MS(ESI+)m/z 371(M+H)+。
Core 35
Racemic-(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -5- (1- methyl -2- oxo -1,2- dihydropyridine -
3- yl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 35A
(E)-tert-butyl 2- (((1- methyl -2- oxo -1,2- dihydropyridine -3- base) methylene) amino) acetic acid esters
At room temperature, to tert-butyl 2- amion acetic acid ester hydrochloride (503mg, 3.00mmol), oxo -1 1- methyl -2-,
2- dihydropyridine -3- formaldehyde (412mg, 3.00mmol) and magnesium sulfate (723mg, 6.01mmol) are in anhydrous CH2Cl2In (5mL)
Triethylamine (420 μ L, 3.01mmol) is added in stirred suspension.Reaction mixture is stirred overnight, with 1: 1 CH2Cl2/ toluene
Flushing liquor filtering, then filtrate is concentrated.Residue is added in toluene, and mixture is filtered by diatomite, uses first
Benzene rinses.Gained filtrate is filtered by filter disc, toluene rinse is used again, is concentrated and is concentrated again from acetonitrile, to provide imines
And its 716mg mixture of dimer.The compound is used in next step without further purification.
Core 35B
Racemic-(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -5- (1- methyl -2- oxo -1,2- dihydropyridine -
3- yl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (49mg, 65 μm of ol) and copper trifluoromethanesulfcomposite (I) benzene
Complex compound (13mg, 26 μm of ol) is placed under nitrogen, and is dissolved in and has been used 45 minutes anhydrous tetrahydro furans of nitrogen jet (2mL)
In.Acquired solution is stirred at room temperature 100 minutes, is cooled down with -10 DEG C of baths, and with core 35A (0.71g, < 3mmol) in tetrahydro
Solution in furans (6mL) is handled dropwise.It adds potassium tert-butoxide (1M in tetrahydrofuran, 60 μ L, 60 μm of ol), after several minutes,
Through 30 minutes addition (E) -3,3- dimethyl -1- nitro but-1-enes (326 μ L, 2.50mmol).Make -10 DEG C of solution through 90 minutes
15 DEG C are warmed to, taken out from cryostat and is stirred at room temperature one week.By reaction mixture 7 kaliumphosphate buffer of 1M pH
(300 μ L) quenching stirs a few minutes with dense aqueous NH4OH (50 μ L) processing, and by addition methyl tertiary butyl ether(MTBE) (8mL) and
Heptane (1mL) is allocated.Organic phase is placed directly on silica, is then extracted the methyl tertiary butyl ether(MTBE) of wet residue
Object is placed on silica, carries out flash chromatography (0 to 20%CH3CN/ methyl tertiary butyl ether(MTBE)) to provide crude product, passed through
Second of chromatography on silica is further purified (in 1: 1 CH2Cl220% to 100% acetic acid second in/heptane
Ester), to provide the chiral enriched fractions (5%, two steps) of 48mg.1H NMR (400MHz, CDCl3)δppm 7.35-7.32
(m, 1H), 7.28-7.25 (m, 1H), 6.18 (dd, J=7.0,6.8Hz, 1H), 5.56 (dd, J=5.5,2.2Hz, 1H),
4.47-4.41 (m, 1H), 3.69-3.65 (m, 1H), 3.57 (s, 3H), 3.21-3.14 (m, 1H), 2.80 (dd, J=6.9,
2.2Hz, 1H), 1.53 (s, 9H), 1.06 (s, 9H)；MS(ESI)m/z 138(M+H)+.
Core 36
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (2- methoxy propane -2- base) -4- nitro -5- Phenylpyrrolidine -
2- formic acid esters
Core 36A
2- methoxyl group -2- methyl propyl- 1- alcohol
2,2- dimethyl ethylene oxide (25g, 347mmol) is dissolved in the CH of 100mL3In OH.Acquired solution is added dropwise to
In the sulfuric acid (10mg, 0.102mmol) in 250-mL2 neck round-bottom flask in the solution in methanol (2.0mL), the round-bottomed flask
It is passed through in air 30 minutes via charging hopper.Due to biggish heat release, flask is put into room-temperature water bath during addition.Add
35 DEG C of internal temperature < are kept during adding.Once addition is completed, solution is just made to flow back 4 hours.Mixture is cooled to environment temperature
Degree, and with KOH in CH3Solution in OH is neutralized to pH 7-7.5 (monitoring using pH meter).By CH3OH is under 35 DEG C of bath temperatures true
Aerial removal, to provide 2- methoxyl group -2- methyl propyl- 1- alcohol (36g, 346mmol).1H NMR (400MHz, chloroform-d) δ ppm
3.41 (d, J=5.7Hz, 2H), 3.21 (d, J=0.7Hz, 3H), 2.20 (t, J=6.1Hz, 1H), 1.14 (s, 6H).
Core 36B
2- methoxyl group -2 methyl propanal
Core 36A (26.77g, 257mmol) is dissolved in methylene chloride (402mL) and is saturated aqueous sodium bicarbonate (268mL)
In mixture.Gained biphase mixture is cooled to 5 DEG C of < in ice-water bath.Add potassium bromide (30.6g, 257mmol) and
TEMPO ((2,2,6,6- tetramethyl piperidine -1- base) oxygroup or oxygen nitrogen free radical, 0.803g, 5.14mmol), then adds more parts
The sodium hypochlorite (10%-15%, 225mL, 3645mmol) of 25-mL.Mixture is extracted with dichloromethane, and by combined extraction
It takes object to be washed with brine, is dried over sodium sulfate, filter and be concentrated in a vacuum, kept for 20 DEG C of bath temperature <.By remaining residue
It distills under atmospheric pressure.The fusing point of the title compound is about 100 DEG C.Fraction containing desired product is merged, to mention
For 2- methoxyl group -2 methyl propanal (6.8g, 66.6mmol).1H NMR (501MHz, chloroform-d) δ ppm 9.59 (s, 1H),
3.31 (s, 3H), 1.28 (s, 6H).
Core 36C
3- methoxyl group-3- methyl-1-nitro butyl- 2- alcohol
Core 36B (4g, 39.2mmol) and nitromethane (3.17mL, 58.7mmol) are dissolved in tetrahydrofuran (10mL) and uncle
In butanol (6mL).After being cooled to 5 DEG C of < in ice bath, be carefully added dropwise in tetrahydrofuran 1M potassium tert-butoxide (3.92mL,
3.92mmol) to avoid any heat release.Mixture is poured into 20mL water, and is extracted with the methyl tertiary butyl ether(MTBE) of 3x20mL.
Combined extract is washed with brine, is dried over sodium sulfate, filters and is concentrated to provide 3- methoxyl group-3- methyl-1-nitro
Butyl- 2- alcohol (4.82g, 25mmol).1H NMR (501MHz, chloroform-d) δ ppm 4.63 (dd, J=12.9,2.4Hz, 1H),
4.45 (dd, J=12.9,9.8Hz, 1H), 4.21 (ddd, J=9.8,6.2,2.4Hz, 1H), 3.26 (s, 3H), 2.83 (d, J=
6.3Hz, 1H), 1.24 (d, J=1.6Hz, 6H).MS(DCI+)m/z 181(M+NH4)+。
Core 36D
(E)-3- methoxyl group-3- methyl-1-nitro but-1-ene
Core 36C (4.6g, 28.2mmol) is dissolved in 40mL anhydrous methylene chloride and solution is cooled to -78 DEG C.Addition
Then mesyl chloride (2.64mL, 33.8mmol) is added dropwise in triethylamine (9.82mL, 70.5mmol).By reaction mixture same
At a temperature of stir 2 hours, then allow to be warmed to environment temperature.Mixture is used and is saturated aqueous sodium bicarbonate and salt water washing,
It is dried over sodium sulfate, filters, be concentrated in a vacuum, and via flash column chromatography, 0-20% second is used on 40g silicagel column
Acetoacetic ester/heptane elutes 20 minutes, to provide the desired product of 2.66g.1H NMR (400MHz, chloroform-d) δ ppm
7.20 (d, J=13.4Hz, 1H), 7.08 (d, J=13.4Hz, 1H), 3.27 (d, J=0.7Hz, 3H), 1.40 (s, 6H)；MS
(ESI+)m/z 163(M+NH4)+。
Core 36E
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (2- methoxy propane -2- base) -4- nitro -5- Phenylpyrrolidine -
2- formic acid esters
The 1.5M solution of lithium bromide (14.25mL, 21.38mmol) is added to (E)-tert-butyl 2- (benzylideneamino) second
Acid esters (core 1A, 3.0g, 12.72mmol) in the solution in anhydrous tetrahydro furan (46mL), and by gained mixture with dry ice/
Acetone bath is cooling.It is slowly added solution of the core 36D (1.847g, 12.72mmol) in tetrahydrofuran (4.9mL), is then added dropwise
2,3,4,6,7,8,9,10- octahydro pyrimido [1,2-a] azepines(2.56mL, 16.99mmol).Exist by reaction mixture
After about -78 DEG C are stirred one hour, dry ice is taken out from bath and bath is made within 60 minutes to be warmed to -15 DEG C, and again through 60 minutes
It is warmed to 0 DEG C.Cryostat is removed, reaction mixture is stirred at room temperature 15 minutes, and adds the aqueous NH of saturation4Cl (50mL),
It is rinsed with methyl tertiary butyl ether(MTBE) (50mL).Biphase mixture is thoroughly stirred and is then diluted with salt water (50mL).By aqueous phase separation
And it is extracted twice with methyl tertiary butyl ether(MTBE), and combined organic phase is washed with brine, dry (Na2SO4), filter and be concentrated with
Residue is obtained, which is ground with 40mL heptane and is stored 16 hours at ambient temperature.Obtained solid is filtered.It will
Filtrate is concentrated and is loaded on 12g column, with gradient elution 20 minutes of 0-60% ethyl acetate/heptane, with filtered solid
Merge to provide racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (2- methoxy propane -2- base) -4- nitro -5- phenylpyrrole
Alkane -2- formic acid esters, 1975 (2 .45g, 6.72mmol, 52.8% yield).1H NMR (501MHz, chloroform-d) δ ppm 7.40-
7.29 (m, 5H), 5.36 (dd, J=6.0,2.2Hz, 1H), 4.58 (s, 1H), 3.96 (d, J=6.6Hz, 1H), 3.27 (s,
3H), 3.04 (dd, J=6.7,2.2Hz, 1H), 1.57 (s, 9H), 1.35 (s, 3H), 1.31 (s, 3H)；MS(ESI+)m/z 365
(M+H)+。
Core 37
(2S, 3R, 4S, 5S)-tert-butyl 3- (2- methoxy propane -2- base) -4- nitro -5- Phenylpyrrolidine -2- formic acid
Ester
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.169g, 0.224mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.056g, 0.112mmol) is dissolved in the tetrahydrofuran (28mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature, and adds (E)-tert-butyl 2- (benzal
Amino) solution of the acetic acid esters (4.15g, 18.95mmol) in 5mL tetrahydrofuran, and acquired solution is cooling in ice-water bath
To 5 DEG C of <.The 2- methyl propyl- 2- potassium alcoholate (1M in tetrahydrofuran, 0.177mL, 0.177mmol) in tetrahydrofuran is added dropwise,
Then through 10 minutes (E)-3- methoxyl group-3- methyl-1-nitro but-1-enes (2.5g, 17.22mmol) of the addition from core 36D,
Temperature is kept to be lower than 7 DEG C.Reaction mixture is stirred 45 minutes at 0 DEG C.By mixture 50mL be saturated aqueous ammonium chloride and
The quenching of 75mL ether, and it is warmed to environment temperature.Ether layer is separated, is washed twice with aqueous ammonium chloride washed is saturated, then uses salt water
Washing, and filtered by silicagel pad.Mixture is concentrated to provide rough material, which is diluted simultaneously with normal heptane (50mL)
Chromatography is carried out using 40g silicagel column, with 0-50% heptane/ethyl acetate gradient elution 20 minutes, to provide crude product, by this
Crude product is precipitated in 100mL heptane to provide (2S, 3R, 4S, 5S)-tert-butyl 3- (2- methoxy propane -2- base) -4- nitre
Base -5- Phenylpyrrolidine -2- formic acid esters (3.33g, 9.14mmol, 53.1% yield).1H NMR (400MHz, chloroform-d) δ ppm
7.41-7.23 (m, 5H), 5.36 (dd, J=5.9,2.2Hz, 1H), 4.62-4.52 (m, 1H), 4.00-3.91 (m, 1H), 3.27
(s, 3H), 3.04 (dd, J=6.7,2.2Hz, 1H), 1.57 (s, 9H), 1.34 (s, 3H), 1.31 (s, 3H).；MS(APCI+)m/
z 365(M+H+).Absolute stereochemistry is confirmed by X-ray diffraction analysis.
Core 38
(2S, 3R, 4S, 5S)-tert-butyl 5- (2- (dimethylamino) pyridin-3-yl) -3- (2- methoxy propane -2-
Base) -4- nitro-pyrrole alkane -2- formic acid esters
Core 38A
(E)-tert-butyl 2- (((2- (dimethylamino) pyridin-3-yl) methylene) amino) acetic acid esters
Tert-butyl 2- amion acetic acid ester hydrochloride (2.411g, 14.38mmol) and magnesium sulfate (3.46g, 28.8mmol) is outstanding
Float in methylene chloride (23.97mL), and by suspension 2- (dimethylamino) cigarette aldehyde (2.16g, 14.38mmol) He Sanyi
Amine (2.005mL, 14.38mmol) processing.Mixture is stirred at ambient temperature 16 hours.By solid material filtration, and will
Filtrate water washing.By organic matter removal and use Na2SO4It is dry, it filters, is then concentrated with offer (E)-tert-butyl 2- again
(((2- (dimethylamino) pyridin-3-yl) methylene) amino) acetic acid esters (4.06g, 15.42mmol, 107% yield).1H
NMR (400MHz, chloroform-d) δ ppm 8.38 (s, 1H), 8.29 (dd, J=4.8,2.0Hz, 1H), 8.10 (dd, J=7.6,
2.0Hz, 1H), 6.87 (dd, J=7.5,4.8Hz, 1H), 4.34 (d, J=1.2Hz, 2H), 3.01 (s, 6H), 1.52 (s, 9H)；
MS(ESI+)m/z 264(M+H)+。
Core 38B
(2S, 3R, 4S, 5S)-tert-butyl 5- (2- (dimethylamino) pyridin-3-yl) -3- (2- methoxy propane -2-
Base) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.034g, 0.045mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.011g, 0.022mmol) is dissolved in the tetrahydrofuran (5mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature, and adds (E)-tert-butyl 2- (((2- (two
Methylamino) pyridin-3-yl) methylene) amino) acetic acid esters (0.998g, 3.79mmol) is molten in 0.574mL tetrahydrofuran
Liquid.Acquired solution is cooled to 5 DEG C of < in ice-water bath.Be added dropwise in tetrahydrofuran 2- methyl propyl- 2- potassium alcoholate (0.09mL,
0.090mmol), then through 10 minutes addition (E)-3- methoxyl group-3- methyl-1-nitro but-1-enes (0.5g, 3.44mmol),
Temperature is kept to be lower than 7 DEG C.Reaction mixture is stirred 45 minutes at 0 DEG C.By mixture 3mL be saturated aqueous ammonium chloride and
The quenching of 10mL ether, and it is warmed to environment temperature.Ether layer is separated, is washed twice with aqueous ammonium chloride washed is saturated, then uses salt water
Washing, and filtered by silicagel pad.Filtrate is concentrated and is purified by using the chromatography of 40g silicagel column, 0-50% is used
Heptane/ethyl acetate gradient elution 20 minutes, with offer (2S, 3R, 4S, 5S)-tert-butyl 5- (2- (dimethylamino) pyrrole
Pyridine -3- base) -3- (2- methoxy propane -2- base) -4- nitro-pyrrole alkane -2- formic acid esters (0.98g, 2.399mmol, 69.6%
Rate).1H NMR (501MHz, chloroform-d) δ ppm 8.28 (dd, J=4.8,1.8Hz, 1H), 7.62 (ddd, J=7.6,1.8,
0.9Hz, 1H), 6.96 (dd, J=7.6,4.8Hz, 1H), 5.69 (dd, J=5.7,2.2Hz, 1H), 4.76 (s, 1H), 3.94
(d, J=6.6Hz, 1H), 3.28 (s, 3H), 3.14 (s, 1H), 3.02 (dd, J=6.7,2.1Hz, 1H), 2.84 (s, 6H),
1.56 (s, 9H), 1.36 (s, 3H), 1.31 (s, 3H)；MS(APCI+)m/z 409(M+H+).
Core 39
(2S, 3R, 4S, 5S)-tert-butyl 3- (2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) -4- nitre
Base pyrrolidines -2- formic acid esters
Core 39A
(E)-tert-butyl 2- (((2- methoxypyridine -3- base) methylene) amino) acetic acid esters
By glycine tert-butyl hydrochloride (1.350g, 8.05mmol) and magnesium sulfate (1.494g, 12.41mmol) in dichloro
Mixture in methane (12.0mL) is handled with triethylamine (1.122mL, 8.05mmol), is stirred 30 minutes, and with 2- methoxyl group
Solution processing of the cigarette aldehyde (0.92g, 6.71mmol) in 3mL methylene chloride.Reaction is stirred at room temperature overnight.Mixture is used
Methylene chloride is shifted and is filtered to remove solid.Solid is washed with methylene chloride.Combined filtrate water (5mL) is washed.
These layers are separated, and water layer 5mL methylene chloride is extracted.Combined dichloromethane layer is dried over sodium sulfate, filtering is simultaneously
Concentration with provide (E)-tert-butyl 2- (((2- methoxypyridine -3- base) methylene) amino) acetic acid esters (1.52g, 6.07mmol,
91% yield).1H NMR (501MHz, chloroform-d) δ ppm 8.73 (s, 1H), 8.05 (dd, J=7.7,1.8Hz, 1H), 7.42
(ddd, J=8.3,7.3,1.8Hz, 1H), 7.06-6.96 (m, 1H), 6.93 (dd, J=8.4,0.9Hz, 1H), 4.34 (d, J=
1.3Hz, 2H), 3.90 (s, 3H), 1.52 (s, 9H).
Core 39B
(2S, 3R, 4S, 5S)-tert-butyl 3- (2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) -4- nitre
Base pyrrolidines -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.034g, 0.045mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.011g, 0.022mmol) is dissolved in the tetrahydrofuran (5mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature, and adds (E)-tert-butyl 2- (((2- first
Oxygroup pyridin-3-yl) methylene) amino) solution of the acetic acid esters (0.948g, 3.79mmol) in 0.574mL tetrahydrofuran.It will
Acquired solution is cooled to 5 DEG C of < in ice-water bath.Be added dropwise in tetrahydrofuran 2- methyl propyl- 2- potassium alcoholate (0.09mL,
0.090mmol), then temperature is kept to be lower than 7 DEG C through 10 minutes addition core 36D (0.5g, 3.44mmol).By reaction mixture
It is stirred 45 minutes at 0 DEG C.Reaction 3mL is saturated aqueous ammonium chloride and 10mL diethyl ether quenches, and is warmed to environment temperature.It will
Ether layer separation is washed twice with aqueous ammonium chloride washed is saturated, is then washed with brine.Organic layer is concentrated to provide thick residue,
And purified by using the chromatography of 12g silicagel column, with 0-50% heptane/ethyl acetate gradient elution 20 minutes, with
(2S, 3R, 4S, 5S)-tert-butyl 3- (2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) -4- nitro pyrrole is provided
Cough up alkane -2- formic acid esters (0.77g, 1.947mmol, 56.5% yield).1H NMR (400MHz, chloroform-d) δ ppm 8.11 (ddd,
J=5.0,1.8,0.6Hz, 1H), 7.56 (ddd, J=7.3,1.8,1.0Hz, 1H), 6.88 (dd, J=7.4,5.0Hz, 1H),
5.54 (dd, J=5.8,2.3Hz, 1H), 4.58 (s, 1H), 4.02 (s, 3H), 3.87 (d, J=6.9Hz, 1H), 3.27 (s,
3H), 3.20 (s, 1H), 3.04 (dd, J=7.0,2.3Hz, 1H), 1.55 (s, 9H), 1.33 (s, 3H), 1.28 (s, 3H)；MS
(APCI+)m/z 396(M+H+)。
Core 40
(2S, 3R, 4S, 5S)-tert-butyl 5- (2- methoxyphenyl) -3- (2- methoxy propane -2- base) -4- nitro-pyrrole
Alkane -2- formic acid esters
Core 40A
(E)-tert-butyl 2- ((2- benzylidene) amino) acetic acid esters
By glycine tert-butyl hydrochloride (1.35g, 8.05mmol) and magnesium sulfate (1.494g, 12.42mmol) in CH2Cl2
Mixture in (12.0mL) (anhydrous) is handled with triethylamine (1.122mL, 8.05mmol), is stirred 15 minutes, and with 2- methoxy
Benzaldehyde is in CH2Cl2Solution processing in (about 3mL).Bottle is covered and is stirred at room temperature overnight mixture.It will mix
Close object CH2Cl2It shifts and filters to remove solid.By solid CH2Cl2Washing.Combined filtrate water (5mL) is washed.
By these layers of separation and by water layer CH2Cl2(about 5mL) extraction.By combined CH2Cl2Layer is dried over sodium sulfate, and is filtered, dense
Contracting, and it is directly entered next step.1H NMR (501MHz, chloroform-d) δ ppm 8.73 (s, 1H), 8.05 (dd, J=7.7,
1.8Hz, 1H), 7.42 (ddd, J=8.3,7.3,1.8Hz, 1H), 7.06-6.96 (m, 1H), 6.93 (dd, J=8.4,0.9Hz,
1H), 4.34 (d, J=1.3Hz, 2H), 3.90 (s, 3H), 1.52 (s, 9H).
Core 40B
(2S, 3R, 4S, 5S)-tert-butyl 5- (2- methoxyphenyl) -3- (2- methoxy propane -2- base) -4- nitro-pyrrole
Alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.034g, 0.045mmol) and copper trifluoromethanesulfcomposite
(II) (0.011g, 0.022mmol), which is dissolved in, has used N2Stream sprays in 1 hour tetrahydrofuran (5mL).Gained mixture is existed
1 hour (continuing nitrogen jet) is stirred at room temperature and adds (E)-tert-butyl 2- ((2- benzylidene) amino) acetic acid esters
The solution of (0.945g, 3.79mmol) in 0.574mL tetrahydrofuran, and acquired solution is cooled to 5 DEG C of < in ice-water bath.
The 2- methyl propyl- 2- potassium alcoholate (0.177mL, 0.177mmol) in tetrahydrofuran is added dropwise, then through 10 minutes addition (E) -3- first
Oxygroup-3- methyl-1-nitro but-1-ene (0.5g, 3.44mmol) keeps temperature to be lower than 7 DEG C.By reaction mixture at 0 DEG C
Stirring 45 minutes.Mixture 3mL is saturated aqueous ammonium chloride and 10mL ether quenches, and is warmed to room temperature.Ether layer is separated,
It is washed twice with aqueous ammonium chloride washed is saturated, is then washed with brine, and filtered by silicagel pad.Filtrate is concentrated thick residual to provide
Excess, and purified by using the chromatography of 40g silicagel column, divided with 0-50% heptane/ethyl acetate gradient elution 20
Clock, to provide (2S, 3R, 4S, 5S)-tert-butyl 5- (2- methoxyphenyl) -3- (2- methoxy propane -2- base) -4- nitro pyrrole
Cough up alkane -2- formic acid esters (0.71g, 1.800mmol, 52.3% yield).1H NMR (400MHz, chloroform-d) δ ppm 7.32-7.29
(m, 1H), 7.28-7.23 (m, 1H), 6.96 (t, J=7.5Hz, 1H), 6.89 (d, J=8.2Hz, 1H), 5.55 (dd, J=
5.8,2.4Hz, 1H), 4.68 (d, J=5.8Hz, 1H), 3.91 (s, 3H), 3.86 (d, J=7.1Hz, 1H), 3.32 (bs, 1H),
3.27 (s, 3H), 3.07 (dd, J=7.1,2.5Hz, 1H), 1.57 (s, 9H), 1.33 (s, 3H), 1.29 (s, 3H)；MS(APCI
+)m/z 395(M+H)+。
Core 41
(2S, 3R, 4S, 5S)-ethyl 4- nitro -5- phenyl -3- (1- (trifluoromethyl) cyclopropyl) pyrrolidines -2- formic acid esters
Core 41A
N- methoxy-. N-methyl -1- (trifluoromethyl) cyclopropane carboxamide
At 10 DEG C, through 1 hour, to 1- (trifluoromethyl) cyclopropane-carboxylic acid (29.5g, 191.56mmol) in methylene chloride
1,1 '-carbonyl dimidazoles (40.96g, 252.86mmol) are added batch-wise in solution in (580mL), reaction temperature is kept to be lower than
20℃.The addition of 1,1 '-carbonyl dimidazoles is slight exotherm, and releases CO2Gas.Reaction is stirred at room temperature 30 points
Then clock adds triethylamine (37.1mL, 268.19mmol), then adds N, O- dimethyl hydroxylamine hydrochloride (26.16g,
268.19mmol).Gained mixture is stirred 15 hours, then reversed quenching to cooling (5 DEG C) 3N HCL aqueous solution
In (200mL).Organic layer is successively washed with saturation aqueous sodium bicarbonate (200mL) and water (200mL), and dense under reduced pressure
Contracting, with provide title compound N- methoxy-. N-methyl -1- (trifluoromethyl) cyclopropane carboxamide (31.32g,
158.98mmol, 83% yield), purity, which is enough to be employed without, to be further purified.1H NMR (400MHz, CDCl3)δppm
3.75 (s, 3H), 3.29 (s, 3H), 1.24-1.33 (m, 4H).
Core 41B
1- (trifluoromethyl) cyclopanecarboxaldehyde
At 0 DEG C, under an inert atmosphere, with vigorous stirring, through 3 minutes to powdered hydrogenated aluminium lithium (6.36g,
The N- methoxy-. N-methyl-in diethyl ether (50mL) 167.5mmol) is added dropwise in the solution in anhydrous diethyl ether (165mL)
1- (trifluoromethyl) cyclopropane carboxamide (33g, 167.5mmol).Reaction is stirred 1 hour at the same temperature, and carefully
It is quenched dropwise with water (14.85mL), 15% aqueous NaOH (14.85mL), water (14.85mL) in addition.Slurries are passed through into diatom
Soil pad is filtered and is washed with diethyl ether (2x150mL).At 0 DEG C, the property of will volatilize solvent carefully removes under reduced pressure, to provide
Title compound 1- (trifluoromethyl) cyclopanecarboxaldehyde (12.7g, 92.13mmol, 55.0% yield) will due to its volatility
It is without further purification i.e. in next step.1H NMR (400MHz, CDCl3) δ ppm 9.69 (s, 1H), 1.20-1.46
(m, 4H).
Core 41C
2- nitro -1- (1- (trifluoromethyl) cyclopropyl) ethyl alcohol
At 0 DEG C, dripped in the slurries in anhydrous tetrahydro furan (200mL) to lithium aluminium hydride reduction (641mg, 16.89mmol)
Add nitromethane (45.6mL, 844.2mmol).Mixture is stirred 30 minutes at 0 DEG C, and 1- (trifluoromethyl) cyclopropyl is added dropwise
Alkane formaldehyde (23.3g, 168.84mmol).Mixture is stirred 2 hours at 0 DEG C and is quenched with the aqueous HCl of 1N (100mL), is inclined
It pours into water (150mL), and is extracted with methylene chloride (2x150mL).Combined organic layer is washed with salt water (2x100mL),
It is dried over sodium sulfate, filters and be concentrated to provide title compound 2- nitro -1- (1- (trifluoromethyl) cyclopropyl) ethyl alcohol
(21.17g, 106.38mmol, 63.0% yield).1H NMR (400MHz, CDCl3) δ ppm 4.33-4.68 (m, 4H), 0.92-
1.08 (m, 4H).
Core 41D
(E) -1- (2- nitroethenyl group) -1- (trifluoromethyl) cyclopropane
At -10 DEG C, under an inert atmosphere, to 2- nitro -1- (1- (trifluoromethyl) cyclopropyl) ethyl alcohol (21.0g,
106.4mmol) trifluoroacetic anhydride (16.52mL, 117.2mmol) is added in the solution in methylene chloride (200mL).It will mixing
Object stirs 5 minutes at -15 DEG C, then adds triethylamine (32.61mL, 234.08mmol), kept during addition bath temperature -
15℃.It is persistently stirred at -10 DEG C 45 minutes.Will reaction by TLC (with iodine staining and UV) monitoring and with saturated ammonium chloride water
Solution (150mL) quenching.Mixture methylene chloride (150mL) is diluted and stirred 5 minutes.By water layer methylene chloride
(100mL × 2) extraction.Combined organic layer is dried over magnesium sulfate, filtering, and be concentrated.Residue is passed through into silica gel column chromatography
Method (elutes) purifying with 1/300 ethyl acetate/petroleum ether, to provide title compound (E) -1- (2- nitroethenyl group) -1-
(trifluoromethyl) cyclopropane (11.2g, 61.88mmol, 58.1% yield).1H NMR (400MHz, CDCl3) δ ppm 7.14 (d, J
=13.6Hz, 1H), 7.02 (d, J=14.0Hz, 1H), 1.58-1.62 (m, 2H), 1.20-1.22 (m, 2H).
Core 41E
(2S, 3R, 4S, 5S)-ethyl 4- nitro -5- phenyl -3- (1- (trifluoromethyl) cyclopropyl) pyrrolidines -2- formic acid esters
Under an inert atmosphere, to containing activationTrifluoro is added in MS and the flame-dried Schlenk pipe of stirring rod
It copper methane sulfonate (I) dimer benzene complex (193mg, 0.384mmol), catalyst 1 (274mg, 0.364mmol) and newly distills
Anhydrous tetrahydro furan (40mL).Mixture is stirred at room temperature 15 minutes and is cooled to 0 DEG C.(E)-second is added into mixture
Base 2- (benzylideneamino) acetic acid esters (core 22A, 4.12g, 21.54mmol), potassium tert-butoxide (37.18mg, 0.332mmol) and
(E) -1- (2- nitroethenyl group) -1- (trifluoromethyl) cyclopropane (3.0g, 16.56mmol).Mixture is stirred 2 at 0 DEG C
Hour is simultaneously filtered by short silica gel plug.Filtrate is concentrated under reduced pressure.By residue by silica gel column chromatography (with 1/10 stone
Oily ether/ethyl acetate elution) purifying, to provide title compound (2S, 3R, 4S, 5S)-ethyl 4- nitro -5- phenyl -3- (1-
(trifluoromethyl) cyclopropyl) pyrrolidines -2- formic acid esters (3.45g, 9.28mmol, 68% yield).1H NMR (400MHz, CDCl3)
δ ppm 7.29-7.38 (m, 5H), 5.43-5.45 (m, 1H), 4.60-4.64 (m, 1H), 4.31-4.37 (m, 2H), 3.88 (t, J
=8.4Hz, 1H), 3.12 (t, J=9.6Hz, 1H), 2.99-3.02 (m, 1H), 1.37 (t, J=6.8Hz, 3H), 1.15-1.22
(m, 2H), 0.87-0.95 (m, 2H)；LC-MS(ESI+)m/z 373(M+H)+。
Core 42
(2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -4- nitro -5- Phenylpyrrolidine -2- first
Acid esters
Core 42A
Two rings [1.1.1] pentane -1- base methanol
At 0 DEG C, Xiang Erhuan [1.1.1] pentane -1- formic acid (4.0g, 35.7mmol) is molten in tetrahydrofuran (89mL)
Lithium aluminium hydride reduction (1.801g, 47.4mmol) is added batch-wise in liquid, which is acutely bubbled.Reaction is warmed to 24 DEG C and stirs 16
Hour.It will react cooling in ice bath, 4g sal glauberi is added batch-wise, is stirred to react 1 hour.Add NaOH aqueous solution
Reaction mixture is stirred 0.5 hour, is added water (2mL) by (15%, 2mL), is removed ice bath and is stirred the mixture for 2 hours.It will
Mixture is dry with 40g anhydrous sodium sulfate.Suspension is filtered and washs filtrate with ether.Solvent is removed in a vacuum, with
Thick two rings [1.1.1] pentane -1- base methanol (3.2g, 32.6mmol, 91% yield) is provided.1H NMR (501MHz, chloroform-
D) δ ppm 3.56 (s, 2H), 2.57 (s, 1H), 1.77 (s, 6H).
Core 42B
Two rings [1.1.1] pentane -1- formaldehyde
The oxalyl chloride (4.57mL, 52.2mmol) being enclosed in 250-mL round-bottomed flask in 55mL methylene chloride, and will
Flask is cooled to < -70 DEG C in acetone-dry ice bath.Through 20 minutes dropwise addition dimethyl sulfoxides (7.40mL, 104mmol), keep
< -60 DEG C of temperature.After the completion of addition, acquired solution is stirred at the same temperature 15 minutes, after through 30 minutes two rings of addition
Solution of [1.1.1] pentane -1- base methanol (core 42A, 3.2g, 32.6mmol) in methylene chloride (5mL) keeps temperature < -
65℃.After the completion of addition, reaction mixture (suspension) is stirred at the same temperature 1 hour (allows to warm and is no more than -60
DEG C), the pure triethylamine (22.72mL, 163mmol) at -78 DEG C was added through 10 minutes at this time.Generate very thick slurry
Liquid.Flask is taken out from ice bath.It is after reaching environment temperature, reaction mixture is sudden by the aqueous HCl of 1M of addition 200mL
It goes out.These layers are separated, and organic layer is washed twice with the aqueous HCl of 1M (30mL) and salt water, are then dried over sodium sulfate, mistake
Filter and concentration (rotary evaporation bath) at 10 DEG C in a vacuum, with offer two rings [1.1.1] pentane -1- formaldehyde (2.6g,
27.0mmol, 83% yield).1H NMR (501MHz, chloroform-d) δ ppm 9.52 (d, J=0.7Hz, 1H), 2.57 (d, J=
0.8Hz, 1H), 2.11 (s, 6H).
Core 42C
1- (two rings [1.1.1] pentane -1- base) -2- nitroethyl alcohol
Core 42B (2.6g, 27.0mmol) and nitromethane (2.188mL, 40.6mmol) are dissolved in tetrahydrofuran (10mL)
In the tert-butyl alcohol (3mL).After being cooled to 5 DEG C of < in ice bath, potassium tert-butoxide (5.41mL, 5.41mmol) solution is added dropwise.1 hour
Afterwards, ice bath is removed, and is stirred the mixture for 30 minutes.Mixture is poured into 40mL water and is extracted with the ether of 3x30mL.It will
Combined extract is washed with brine, and is dried over sodium sulfate, and is filtered and is concentrated.Via the purifying of flash column chromatography (in 40g silicon
Eluted 20 minutes in rubber column gel column with 0-60% ethyl acetate/heptane) provide desired product 1- (two rings [1.1.1] pentane -1-
Base) -2- nitroethyl alcohol (2.22g, 14.13mmol, 52.2% yield).1H NMR (500MHz, chloroform-d) δ ppm 4.49-
4.38 (m, 1H), 4.36-4.27 (m, 2H), 2.61 (s, 1H), 2.32-2.29 (m, 1H), 1.85-1.78 (m, 6H)；MS(DCI
+)m/z 175(M+NH4+)。
Core 42D
(E) -1- (2- nitroethenyl group) two rings [1.1.1] pentane
Core 42C (2.22g, 14.13mmol) is dissolved in 18.8mL anhydrous methylene chloride and solution is cooled to -78 DEG C.
It adds triethylamine (4.92mL, 35.3mmol), mesyl chloride (1.321mL, 16.95mmol) then is added dropwise.By reaction mixture
It stirs 1 hour, remove the dry ice bath and stirs the mixture for 1 hour at the same temperature.Mixture is saturated aqueous bicarbonate
Sodium and salt water washing, are then dried over sodium sulfate, and filtering is being concentrated in vacuo, and via flash column chromatography, in 24g silicon
It is eluted 20 minutes in rubber column gel column with 0-40% ethyl acetate/heptane, to provide desired product (E) -1- (2- nitroethenyl group)
Two rings [1.1.1] pentane (1.63g, 11.71mmol, 83% yield).1H NMR (501MHz, chloroform-d) δ ppm 7.20 (d, J
=13.4Hz, 1H), 6.88 (d, J=13.4Hz, 1H), 2.62 (s, 1H), 2.04 (s, 6H).
Core 42E
(2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -4- nitro -5- Phenylpyrrolidine -2- first
Acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.065g, 0.086mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.017g, 0.034mmol) is dissolved in the tetrahydrofuran (9.5mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continue nitrogen jet) at ambient temperature, and add core 1A (1.040g,
4.74mmol) the solution in 1mL tetrahydrofuran, and acquired solution is cooled to 5 DEG C of < in ice-water bath.It is added dropwise in tetrahydro furan
2- methyl propyl- 2- potassium alcoholate (0.177mL, 0.177mmol) in muttering, then through 3 minutes addition core 42D (0.6g, 4.31mmol),
Temperature is kept to be lower than 7 DEG C.Reaction mixture is stirred 45 minutes at 0 DEG C.Mixture 6mL is saturated aqueous ammonium chloride and 20mL
Ether quenching, and it is warmed to environment temperature.Ether layer is separated, is washed twice with aqueous ammonium chloride washed is saturated, is then washed with brine,
And it is filtered by silicagel pad.Filtrate is concentrated to provide residue, which is diluted with normal heptane (50mL), it is small to stand 2
When.Mixture is filtered and is precipitated in the hot heptane of 50mL, with offer (2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1]
Pentane -1- base) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (0.73g, 2.037mmol, 47.2% yield).1H NMR(4
((MHz, chloroform-d) δ ppm 7.44-7.30 (m, 5H), 5.01 (dd, J=5.7,2.0Hz, 1H), 4.47 (d, J=5.5Hz,
1H), 3.74 (d, J=6.0Hz, 1H), 3.40 (bs, 1H), 3.02-2.92 (m, 1H), 2.69 (s, 1H), 1.96-1.79 (m,
6H), 1.57 (s, 9H)；MS(ESI+)m/z 359(M+H+).
Core 43
(2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -5- (2- (dimethylamino) pyridine -3-
Base) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.036g, 0.047mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (9.55mg, 0.019mmol) is dissolved in the tetrahydrofuran (4.2mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continue nitrogen jet) at ambient temperature, and add core 38A (0.72g,
2.73mmol) the solution in 1mL tetrahydrofuran, and acquired solution is cooled to 5 DEG C of < in ice-water bath.It is added dropwise in tetrahydro furan
2- methyl propyl- 2- potassium alcoholate (0.050mL, 0.050mmol) in muttering then added the core in 1mL tetrahydrofuran through 2 minutes
42D (0.33g, 2.372mmol) keeps temperature to be lower than 7 DEG C.Reaction mixture is stirred 1 hour at 0 DEG C.By mixture 4mL
It is saturated aqueous ammonium chloride and the quenching of 10mL diethyl ether, and is warmed to environment temperature.Ether layer is separated, with the aqueous ammonium chloride washed of saturation
It washs twice, is then washed with brine, and filtered by silicagel pad.Mixture is concentrated and by using the chromatography of 24g silicagel column
Method is purified, with 0-70% heptane/ethyl acetate gradient elution 20 minutes, with offer (2S, 3R, 4S, 5S)-tert-butyl 3-
(two rings [1.1.1] pentane -1- base) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters
(0.73g, 1.814mmol, 76% yield).1H NMR (501MHz, chloroform-d) δ ppm 8.33 (dd, J=4.9,1.8Hz,
1H), 7.61 (ddd, J=7.8,2.0,0.9Hz, 1H), 7.02 (dd, J=7.6,4.8Hz, 1H), 5.37 (dd, J=5.3,
1.6Hz, 1H), 4.64 (d, J=11.3Hz, 1H), 3.72 (s, 1H), 3.24 (s, 1H), 2.94 (dd, J=6.2,1.3Hz,
1H), 2.82 (s, 6H), 2.70 (s, 1H), 1.97-1.80 (m, 6H), 1.56 (s, 9H)；MS(ESI+)m/z 403(M+H+).
Core 44
(2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -5- (2- methoxypyridine -3- base) -4-
Nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.045g, 0.060mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.012g, 0.024mmol) is dissolved in the tetrahydrofuran (5.0mL) sprayed with nitrogen stream 1 hour
In.Gained mixture is stirred 1 hour (continuing nitrogen jet) at ambient temperature, and adds (E)-tert-butyl 2- (((2- first
Oxygroup pyridin-3-yl) methylene) amino) solution of the acetic acid esters (0.923g, 3.32mmol) in 1mL tetrahydrofuran, and by institute
It obtains solution and is cooled to 5 DEG C of < in ice-water bath.Be added dropwise in tetrahydrofuran 2- methyl propyl- 2- potassium alcoholate (0.063mL,
0.063mmol), then the core 42D (0.42g, 3.02mmol) through addition in 2 minutes in 1mL tetrahydrofuran, holding temperature are lower than
7℃.Reaction mixture is stirred 1 hour at 0 DEG C.Mixture 4mL is saturated aqueous ammonium chloride and 10mL diethyl ether quenches, and
It is warmed to environment temperature.Ether layer is separated, is washed twice, is then washed with brine, and pass through silica gel with aqueous ammonium chloride washed is saturated
Pad filtering.Mixture is concentrated to provide thick residue, and is purified by using the chromatography of 24g silicagel column, 0- is used
60% heptane/ethyl acetate gradient elution 20 minutes, with offer (2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] penta
Alkane -1- base) -5- (2- methoxypyridine -3- base) -4- nitro-pyrrole alkane -2- formic acid esters (0.71g, 1.823mmol, 60.4%
Rate).1H NMR (400MHz, chloroform-d) δ ppm 8.13 (dd, J=5.0,1.8Hz, 1H), 7.55 (ddd, J=7.5,1.9,
1.0Hz, 1H), 6.90 (dd, J=7.4,5.0Hz, 1H), 5.23 (dd, J=5.3,1.7Hz, 1H), 4.46 (s, 1H), 4.03
(s, 3H), 3.68 (d, J=6.0Hz, 1H), 3.30 (s, 1H), 2.92 (dd, J=6.2,1.7Hz, 1H), 2.68 (s, 1H),
1.94-1.79 (m, 6H), 1.55 (s, 9H)；MS(APCI+)m/z 390(M+H+).
Core 45
Racemic-methyl (2R, 3S, 4R, 5R) -3- cyclopropyl -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
Core 45A
Methyl (E) -2- (benzylideneamino) acetic acid esters
By glycine methyl ester hydrochloride (H-Gly-OMe-HCl) (689.1g, 5.49mmol) and magnesium sulfate (751.6mg,
It 6.24mmol) is suspended in methylene chloride (10mL), then adds triethylamine (760 μ L, 5.45mmol), and by mixture in room
Temperature lower stirring 20 minutes.Then benzaldehyde (500 μ L, 4.93mmol) is added dropwise, and reaction is stirred 17 hours at ambient temperature.
After this, mixture is filtered, and by filter bed CH2Cl2Washing.Combined filtrate water is washed twice and is washed with brine
Once, through Na2SO4Be dried, filtered and concentrated with offer (E)-methyl 2- (benzylideneamino) acetic acid esters (1.284g,
7.25mmol, 91% yield).1H NMR (400MHz, chloroform-d) δ ppm 8.31 (d, J=1.4Hz, 1H), 7.79 (dd, J=
7.7,1.9Hz, 2H), 7.49-7.38 (m, 3H), 4.43 (d, J=1.2Hz, 2H), 3.79 (s, 3H)；MS(ESI+)m/z 178
(M+H)+。
Core 45B
1- cyclopropyl -2- nitroethyl alcohol
Tetrahydrofuran (10mL) and the tert-butyl alcohol (10.00mL) are cooled to 0 DEG C, with cyclopanecarboxaldehyde (1.1mL,
14.60mmol) handled with nitromethane (1.18mL, 21.88mmol).It is added dropwise potassium tert-butoxide (1M is in tetrahydrofuran)
Reaction is warmed to room temperature and is stirred overnight by (2.92mL, 2.92mmol).By mixture saturation NH4Cl aqueous solution dilutes simultaneously
Use CH2Cl2Extraction is three times.By combined organic matter through Na2SO4It is dried, filtered and concentrated and (does not heat), contained with providing
The title compound (2.669g, 20.35mmol, 139% yield) of the tert-butyl alcohol.1H NMR (400MHz, CDCl3)δppm 4.62-
4.50 (m, 2H), 3.71 (m, 1H), 2.44 (d, J=4.1Hz, 1H), 0.98 (qt, J=8.2,4.9Hz, 1H), 0.66 (m,
2H), 0.50 (m, 1H), 0.38 (m, 1H).
Core 45C
(E)-(2- nitroethenyl group) cyclopropane
It will be cooling in the 1- cyclopropyl -2- nitroethyl alcohol (core 45B, 2.87g, 21.88mmol) in methylene chloride (30mL)
It is slowly handled to 0 DEG C, and with trifluoroacetic anhydride (3.40mL, 24.07mmol).Then by mixture with triethylamine (6.71mL,
48.1mmol) slowly processing, and reaction is stirred 1.5 hours in ice bath, and is stirred at room temperature 1.5 hours.Then will
Mixture is filtered by silicagel pad, then uses CH2Cl2Washing.It is concentrated combined organic filtrate is not heated, gained is residual
Excess is absorbed in 20% ether-hexane and is filtered with silicagel pad, then is washed with 20% ether-hexane.By combined filtrate without adding
Heat is concentrated.1H NMR (400MHz, CDCl3) δ ppm 7.15 (d, J=13.1Hz, 1H), 6.80 (dd, J=13.2,
10.8Hz, 1H), 1.69-1.60 (m, 1H), 1.18-1.13 (m, 2H), 0.84-0.80 (m, 2H)；MS(DCI+)m/z 131(M+
NH4)+。
Core 45D
Racemic-methyl (2R, 3S, 4R, 5R) -3- cyclopropyl -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
To core 45A (441.2mg, 2.490mmol) and (E)-(2- nitroethenyl group) cyclopropane (core 45C, 257.0mg,
2.272mmol) in the solution in toluene (5mL) and tetrahydrofuran (5mL) add silver acetate (379mg, 2.272mmol) and
Molecular sieve.Reaction mixture is cooled to 0 DEG C, and triethylamine (0.63mL, 4.52mmol) is added slowly to be sufficiently stirred
In reaction mixture.At 0 DEG C after ten minutes, so that reaction is warmed to environment temperature and continue 4 hours.Mixture is filtered and will be consolidated
Body is washed with ethyl acetate.Into combined mixture, addition is saturated aqueous ammonium chloride (30mL), and sediment is filtered out and will be filtered
Liquid is extracted with ethyl acetate (2x35mL).By combined organic fraction through MgSO4It is dried, filtered and concentrated thick to provide 680mg
Material.Crude product is ground from heptane (15mL) and is washed with other heptane (2x15mL) to provide title compound
(391.2mg, 59%).1H NMR (400MHz, DMSO-d6) δ ppm 7.41-7.17 (m, 5H), 5.28 (dd, J=6.8,
3.8Hz, 1H), 4.78 (dd, J=9.5,6.8Hz, 1H), 3.76 (dd, J=8.2,7.1Hz, 1H), 3.71 (s, 3H), 3.52-
3.43 (m, 1H), 2.37-2.27 (m, 1H), 1.11-0.98 (m, 1H), 0.58-0.38 (m, 2H), 0.31-0.17 (m, 2H).MS
(ESI+)m/z 291(M+H)+。
Core 46
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- cyclopropyl -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
Will in toluene (8mL) and tetrahydrofuran (8.00mL) (E)-(2- nitroethenyl group) cyclopropane (core 45C,
0.575g, 5.08mmol), (E)-tert-butyl 2- (benzylideneamino) acetic acid esters (core 1A, 0.929g, 4.24mmol), silver acetate
(1.061g, 6.35mmol) and powdered activationSieve is cooled to 0 DEG C, and with triethylamine (1.5mL, 10.76mmol) by
Drop processing.By mixture from 0 DEG C of stirring to ambient temperature overnight.Then reaction mixture is filtered by diatomite, and filter bed is used
Ethyl acetate washing.Combined filtrate is saturated NH with 40mL4The processing of Cl aqueous solution, and mixture is transferred to separatory funnel
In.Mixture is extracted with ethyl acetate twice, and by combined organic matter through Na2SO4It dries, filters and is concentrated in a vacuum.
Crude product is purified by silica gel chromatography, 0 to 40% ethyl acetate-heptane of use elution, to provide title compound 0.615g
(44% yield).1H NMR (400MHz, DMSO-d6) δ ppm 7.35-7.23 (m, 5H), 5.30 (dd, J=6.5,3.3Hz,
1H), 4.78 (dd, J=10.9,6.4Hz, 1H), 3.65 (dd, J=8.9,6.8Hz, 1H), 3.38-3.28 (m, 1H), 2.22
(m, 1H), 1.47 (s, 9H), 1.07 (m, 1H), 0.60-0.45 (m, 2H), 0.29 (m, 2H)；MS(ESI+)m/z 332.9(M+
H)+。
Core 47
Racemic-(2R, 3S, 4R, 5R) -4- nitro -3- tert-butyl -5- (2- dimethyl-amino-phenyl)-pyrrolidines -2-
Methyl formate
By glycine methyl ester hydrochloride (925mg, 7.37mmol, 1.1 equivalent) be added to triethylamine (1.07mL,
8.04mmol, 1.2 equivalents) in the solution in toluene (20mL).Reaction mixture is existedIt is stirred 30 minutes on molecular sieve.Add
Add 2- dimethylamino-benzaldehyde (1.00g, 6.70mmol, 1.0 equivalent), and reaction mixture is stirred at room temperature overnight.
Reaction mixture is filtered, with dilution with toluene and is cooled to 0 DEG C.Add AgCO2CH3(783mg, 4.69mmol, 0.7 equivalent), so
(E) -3,3- dimethyl -1- nitro but-1-ene (606mg, 4.69mmol, 0.7 equivalent) and triethylamine (0.623mL) are added afterwards.
Will reaction stir 1 hour at 0 DEG C, warm to room temperature, stir 5 hours, and be saturated NH4The quenching of Cl aqueous solution.Add dichloro
Methane and water.By aqueous phase separation and it is extracted with dichloromethane.By combined organic phase Na2SO4It is dried, filtered and concentrated to dry.
Rough material is purified by flash chromatography (cyclohexane/ethyl acetate 100/0 to 60/40), to provide title compound (warp
Two steps, 489mg, 21%).LC/MS(ESI+)m/z 350.35(M+H)+。
Core 48
Racemic-(2R, 3S, 4R, 5S) -4- nitro -3- tert-butyl -5- (6- methoxv-pyridine -2- base)-pyrrolidines -2-
Methyl formate
Core 48A
(E)-methyl 2- (((6- methoxypyridine -2- base) methylene) amino) acetic acid esters
By glycine methyl ester hydrochloride (925mg, 7.37mmol, 1.1 equivalent) be added to triethylamine (1.07mL,
8.04mmol, 1.2 equivalents) in the solution in toluene (20mL).Reaction mixture is existedIt is stirred 30 minutes on molecular sieve.So
6- methoxyl group -2- pyridine carboxaldehyde (0.92g, 6.70mmol, 1.0 equivalent) is added afterwards, and reaction mixture is stirred at room temperature
Overnight.Reaction mixture is filtered, with dilution with toluene and is cooled to 0 DEG C, is used for next step without further purification.
Core 48B
Racemic-(2R, 3S, 4R, 5S) -4- nitro -3- tert-butyl -5- (6- methoxv-pyridine -2- base)-pyrrolidines -2-
Methyl formate
AgCO is added into the solution of core 48A2CH3(783mg, 4.69mmol, 0.7 equivalent) then adds (E) -3,3- bis-
Methyl-1-nitro but-1-ene (606mg, 4.69mmol, 0.7 equivalent) and triethylamine (0.623mL).It will react and stir 1 at 0 DEG C
Hour, it then elevates the temperature to room temperature.Will reaction stirring 5 hours, and be saturated NH4The quenching of Cl aqueous solution.Add dichloromethane
Alkane and water.By aqueous phase separation and it is extracted with dichloromethane.Combined organic phase is dried, filtered and concentrated to dry.By rough material
Purified by flash chromatography (cyclohexane/ethyl acetate 100/0 to 60/40), with provide title compound (through two steps,
987mg, 40%).LC/MS(ESI+)m/z 338.22(M+H)+。
Core 49
Racemic-(2R, 3S, 4R, 5S) -4- nitro -3- tert-butyl -5- pyridine -2- base-pyrrolidines -2- t-butyl formate
Core 49A
(E)-tert-butyl ester 2- ((pyridine -2- methylene) amino) acetic acid esters
Pyridine carboxaldehyde is replaced with 6- methoxynicotinaldehyde, and replaces glycine methyl ester salt with glycine tert-butyl hydrochloride
Hydrochlorate prepares title compound according to program described in core 48A.
Core 49B
Racemic-(2R, 3S, 4R, 5S) -4- nitro -3- tert-butyl -5- pyridine -2- base-pyrrolidines -2- formic acid tert-butyl
At 0 DEG C, by silver acetate (AgCO2CH3, 194mg, 1.16mmol, 1.5 equivalents) be added to core 49A (256mg,
1.16mmol, 1.5 equivalents) in the solution in toluene (0.5mL).Reaction mixture is stirred 10 minutes.It is slowly added (E)-
Solution of 3, the 3- dimethyl -1- nitro but-1-enes (100.0mg, 0.774mmol, 1.0 equivalent) in toluene (0.5mL), then
(174 μ L, 1.16mmol, 1.5 work as 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene of the dropwise addition in toluene (0.5mL)
Amount).Reaction mixture is stirred at room temperature overnight, and with saturation NH4The quenching of Cl aqueous solution.Add methylene chloride and water.It will
Water phase extraction, and combined organic phase is dried, filtered and concentrated.Rough material is passed through into flash chromatography (hexane/ethyl acetate
100/0 to 50/50) it purifies, to provide title compound (271mg, 100%).LC/MS(ESI+)m/z 350.23(M+H)+。
Core 50
Racemic-(2S, 3R, 4S, 5R) -4- nitro -3- tert-butyl -5- (3- methoxv-pyridine -2- base)-pyrrolidines -2-
Methyl formate
Methyl 2- amion acetic acid ester hydrochloride (1.1g, 8.75mmol, 1.2 equivalent) is suspended in dry toluene (25mL)
In, and add triethylamine (2.24mL, 16.04mmol, 2.2 equivalent).It stirs the mixture for about 10 minutes.Add 3- methoxyl group pyrrole
Pyridine -2- formaldehyde (1g, 7.29mmol, 1.00 equivalent), and mixture is stirred at room temperature 2 hours.Gained mixture is filtered,
And filtrate is cooled to 0 DEG C in ice bath.It adds triethylamine (1017.7 μ L, 1 equivalent).Add (E) -3,3- dimethyl -1- nitre
Base but-1-ene (706mg, 5.47mmol, 0.75 equivalent) then adds silver acetate (AgCO2CH3, 1.22g, 7.29mmol, 1.00
Equivalent).After 2 hours, reaction is quenched with aqueous ammonium chloride solution.Reaction mixture is extracted with dichloromethane.It will be organic laminated
And hydrophobic glass material is made it through, and be concentrated in a vacuum.Rough material is passed through into flash chromatography (cyclohexane/ethyl acetate
100/0 to 40/60) it purifies, to provide title compound (through 2 steps, 625mg, 25%).LC/MS(ESI+)m/z
338.24(M+H)+。
Core 51
Tert-butyl (2S, 3S, 4R, 5S) -3- tert-butyl -4- nitro -5- phenyl-pyrrolidin -2- formic acid esters
In N2Under, Xiang Peiti (S) -1- (diphenylphosphino) -2- [(S) -4- isopropyl oxazoline -2- base] ferrocene
The solution previously to have deaerated of (CAS# 163169-29-7,20.5mg, 0.04mmol, 0.011 equivalent) in tetrahydrofuran (6mL)
Middle addition trifluoromethanesulfonic acid copper complex (CAS# 42152-46-5,10mg, 0.019mmol, 0.005 equivalent).Reaction is mixed
Object N2Injection 5 minutes.Then by solution at room temperature in N2Lower stirring 45 minutes.Then mixture is cooled to 0 DEG C -5 DEG C
(internal temperature), and add in tetrahydrofuran (1mL) (E)-tert-butyl 2- (benzylideneamino) acetic acid esters (core 1A,
1.096g, 5.0mmol, 1.3 equivalent), keep internal temperature to be lower than 5 DEG C.Be slowly added potassium tert-butoxide (1M in tetrahydrofuran,
310 μ L, 0.31mmol, 0.08 equivalents) solution, then adds (E) -3,3- dimethyl -1- nitro in tetrahydrofuran (1mL)
But-1-ene (500mg, 3.87mmol, 1.0 equivalent).Gained suspension is stirred 20 minutes at 0-5 DEG C.After 30 minutes, pass through
Addition saturation NH4Cl aqueous solution quenches reaction mixture, and is diluted in ethyl acetate.Organic layer is separated, with water and salt
Water washing, through MgSO4It dries, filters and is concentrated in a vacuum.Crude mixture is passed through into flashchromatography on silica gel (heptane/acetic acid second
Ester 98/2 to 80/20) purifying, to provide title compound (940mg, 70%).LC/MS(ESI+)m/z 349.4(M+H)+。
Core 52
Racemic-(2R, 3S, 4R, 5S)-methyl 3- (tert-butyl) -5- (3- chloropyridine -2- base) -4- nitro-pyrrole alkane -2-
Formic acid esters
Methyl 2- amion acetic acid ester hydrochloride (1.06g, 8.48mmol, 1.2 equivalent) is suspended in dry toluene (25mL)
In, it adds triethylamine (2.17mL, 15.5mmol, 2.2 equivalent), and reaction mixture is stirred 10 minutes.Then 3- chlorine is added
Pyridine-2-formaldehyde (1g, 7.06mmol, 1.00 equivalent), and mixture is stirred at room temperature 2 hours.By gained mixture mistake
Filter, and filtrate is cooled to 0 DEG C in ice bath.It adds triethylamine (986 μ L, 7.1mmol, 1 equivalent).Add (E) -3,3- diformazan
Base -1- nitro but-1-ene (684.3mg, 5.30mmol, 0.75 equivalent) then adds silver acetate (AgCO2CH3, 1.18g,
7.06mmol, 1.00 equivalents).After 2 hours, reaction is quenched with aqueous ammonium chloride solution.Reaction mixture methylene chloride is extracted
It takes.So that organic layer is passed through phase separator and is concentrated in a vacuum.Rough material is passed through into flash chromatography (cyclohexane/ethyl acetate
100/0 to 40/60) it purifies, to provide title compound (through 2 steps, 900mg, 37%).LC/MS(ESI+)m/z
342.21(M+H)+。
Core 53
Racemic-(4R, 6R, 7R) -7- amino -5- cyclohexane carbo -6- phenyl -5- aza-spiro [2.4] heptane -4- first
Sour methyl esters
Core 53A
(2- (benzyloxy) -2- oxoethyl) tri-phenyl-phosphorus bromide
By 2- benzyl acetate bromide (6.6mL, 42.1mmol) and triphenylphosphine (11.58g, 44.2mmol) in toluene
Mixture in (200mL) is stirred at room temperature 3 days.Sediment is collected by filtration and is washed with diethyl ether, to provide mark
Inscribe compound (2- (benzyloxy) -2- oxoethyl) tri-phenyl-phosphorus bromide (20g, 40.3mmol, 96% yield).LC/MS(ESI
+)m/z 411(M+H)+。
Core 53B
Benzyl 2- (triphenylphosphanylidene) acetic acid esters
By (2- (benzyloxy) -2- oxoethyl) tri-phenyl-phosphorus bromide (2.00g, 4.07mmol) and NaOH (0.081g,
2.035mmol) in CH2Cl2Solution in (20mL) stirs 1 hour at 25 DEG C.By mixture CH2Cl2(50mL) dilution, and
It is washed with water (30mL).Organic layer is separated and is concentrated, with provide benzyl 2- (triphenylphosphanylidene) acetic acid esters (1.5g,
3.25mmol, 80% yield).1H NMR (400MHz, CDCl3) δ ppm 7.60-7.65 (m, 6H), 7.51-7.54 (m, 4H),
7.42-7.46 (m, 6H), 7.20 (s, 4H), 5.00 (s, 2H), 2.96 (s, 1H)；LC-MS(ESI)m/z 411.1(M+H)+。
Core 53C
1- ethyoxyl cyclopropyl alcohol
By (1- ethyoxyl cyclopropyl oxygroup) trimethyl silane (1.499mL, 7.46mmol) and one drop hydrochloric acid (7.16mg,
0.075mmol) in CH3Solution in OH (6mL) stirs 16 hours at 25 DEG C.Mixture is concentrated to provide title compound 1-
Ethyoxyl cyclopropyl alcohol (0.5g, 4.90mmol, 65.6% yield).1H NMR (400MHz, CDCl3) δ ppm 3.76 (q, J=8Hz,
2H), 1.22 (t, J=8Hz, 4H), 0.93-0.95 (m, 4H).
Core 53D
Benzyl 2- ring propylidene acetic acid esters
At 80 DEG C, to benzyl 2- (triphenylphosphanylidene) acetic acid esters (5g, 11.57mmol) and benzoic acid (0.601g,
4.92mmol) 1- ethyoxyl cyclopropyl alcohol (1.391g, 11.57mmol) is added in the solution in toluene (50mL).By mixture
It stirs 5 hours and is concentrated at 80 DEG C.Residue (on silica gel, is eluted with 5% ethyl acetate/hexane) by column chromatography
Purifying, to provide title compound benzyl 2- ring propylidene acetic acid esters (1.3g, 5.66mmol, 48.9% yield).LC/MS(ESI
+)m/z 1892(M+H)+。
Core 53E
Racemic-(4R, 6S, 7R) -7- benzyl 4- tert-butyl 6- phenyl -5- azaspiro [2.4] heptane -4,7- dicarboxylic acid esters
At -70 DEG C, to (E)-tert-butyl 2- (benzylideneamino) acetic acid esters (core 1A, 1.966g, 7.17mmol) and bromine
Change lithium (0.747g, 8.61mmol) and adds benzyl 2- ring propylidene acetic acid esters in the mixture in tetrahydrofuran (20mL)
(1.8g, 7.17mmol) and 1,11 carbon -7- alkene (1.62mL, 10.76mmol) of 8- diazabicylo [5.4.0].By mixture
After -78 DEG C are stirred 30 minutes, mixture is warmed to 0 DEG C and continues then to continue 2 hours at 25 DEG C in 45 minutes.Reaction is used full
With aqueous NH4Cl (10mL) and water (10mL) quenching.By mixture CH2Cl2(30mL) extraction.By organic layer through Na2SO4It is dry
It is dry, filtering, and be concentrated.Residue is purified into (instrument: Gilson 281 by preparative HPLC；Column: XbridpeTM 21.2*
250mm c18,10um；Mobile phase: A: water (10mmol/L NH4HCO3), B: acetonitrile；Gradient: 55%-65%B in 10 minutes,
Stop at 15 minutes；Flow velocity (mL/ minutes) 25.00；Detection wavelength (nm) 214), with provide title compound (251mg,
0.616mmol, 8.59% yield).1H NMR (400MHz, CDCl3) δ ppm 7.23-7.34 (m, 8H), 6.98-7.01 (m,
2H), 4.67-4.79 (m, 3H), 3.68 (s, 1H), 2.91 (d, J=8Hz, 1H), 1.49 (s, 9H), 1.05-1.08 (m, 1H),
0.92-0.95 (m, 1H), 0.77-0.79 (m, 1H), 0.60-0.63 (m, 1H)；LC-MS(ESI+)m/z 408.2(M+H)+。
Core 53F
Racemic-(4R, 6R, 7R) -5- cyclohexane carbo -6- phenyl -5- aza-spiro [2.4] heptane -4,7- dioctyl phthalate 7-
The benzyl ester 4- tert-butyl ester
Core 53E (408mg, 1mmol, 1.0 equivalent) is dissolved in methylene chloride (10mL), and reaction mixture is cooled to
0℃.(161 μ L, 1.2mmol, 1.2 work as addition diisopropylethylamine (261 μ L, 1.4mmol, 1.5 equivalent) and cyclohexyl acyl chlorides
Amount).At room temperature after 15 minutes, reaction mixture is quenched with aqueous ammonium chloride solution.Two phases were separated and by organic phase true
Aerial concentration.Rough material is purified by flash chromatography (heptane/ethyl acetate 95/5 to 70/30), to provide title compound
Object (445mg, 86%).LC/MS(ESI+)m/z 518.50(M+H)+。
Core 53G
Racemic-(4R, 6R, 7R) -5- cyclohexane carbo -6- phenyl -5- aza-spiro [2.4] heptane -4,7- dioctyl phthalate 4-
The tert-butyl ester
Core 53F (443mg, 0.86mmol, 1 equivalent) is dissolved in 20mL methanol.Pd/C 5% is added, and reaction is mixed
Object is stirred at room temperature 2 hours, then filters over celite.Filter vacuum is concentrated.Obtained solid is suspended in dichloromethane
In alkane and filter.Material is dried under vacuum to provide title compound (275mg, 75%), without further purification by it
I.e. in next step.
Core 53H
Racemic-(4R, 6R, 7R) -7- Benzyoxycarbonylamino -5- cyclohexane carbo -6- phenyl -5- aza-spiro [2.4]
Heptane -4- t-butyl formate
To core 53G (275mg, 0.643mmol, 1.0 equivalent) and triethylamine (108 μ L, 0.772mmol, 1.2 equivalent) in first
In agitating solution in benzene (10mL) add diphenyl phosphoryl azide (CAS# 26386-88-9,152 μ L,
0.708mmol, 1.1 equivalents).It is stirred at room temperature after ten minutes, mixture is flowed back 1 hour.It is added into reflux mixture
Benzyl alcohol (133 μ L, 1.29mmol, 2.0 equivalent), and continue reflux 2 hours.Gained mixture is poured into the aqueous NaOH of 1N
And it is extracted with diethyl ether.Organic phase is washed with brine, through MgSO4It dries, filters and is concentrated under reduced pressure.Residue is passed through
Flash chromatography (heptane/ethyl acetate 90/10 to 60/40) purifying, to provide title compound (182mg, 54%).LC/MS
(ESI+)m/z 533.3(M+H)+。
Core 53I
Racemic-(4R, 6R, 7R) -7- amino -5- cyclohexane carbo -6- phenyl -5- aza-spiro [2.4] heptane -4- first
Tert-butyl acrylate
Added in the solution in methanol (5mL) to core 53H (181mg, 0.34mmol, 1 equivalent) Pd/C 5% (72mg,
0.03mmol, 0.1 equivalent).Reaction mixture is stirred at room temperature 1 hour, is then filtered over celite.Filtrate is concentrated
To dry to provide title compound (142mg, quantitative), it is used in next step without further purification.
Core 54
Ethyl (2S, 3S, 4R, 5S) -3- tert-butyl -4- nitro -5- phenyl-pyrrolidin -2- formic acid esters
By the filtrate concentration in the preparation from core 7, and it is pure to pass through silica gel chromatography (heptane/ethyl acetate 80/20)
Change, to provide title compound (second of diastereoisomer of elution).LC/MS(ESI+)m/z 321.5(M+H)+。
Core 55
The tertiary fourth of racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -2- methyl -4- nitro -5- phenyl-pyrrolidin -2- formic acid
Ester
Core 55A
(S) -2- { [1- phenyl -methyl- (E)-subunit]-amino }-propanoic acid tert-butyl ester
By (L)-alanine tert-butyl ester hydrochloride (CAS# 13404-22-3,3.63g, 20mmol, 1.0 equivalent) and benzene first
Aldehyde (2.03mL, 20mmol, 1 equivalent) is suspended in methylene chloride.Add molecular sieve (8g) and triethylamine (2.78mL, 20mmol,
1 equivalent), and reaction mixture is stood 4 hours in the case where not stirring.It is washed by reaction mixture mistake, and by filter cake with methylene chloride
It washs.Organic layer is washed with water, is dried, filtered and concentrated over sodium sulfate to provide title compound (4.56g, 98%).
Core 55B
The tertiary fourth of racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -2- methyl -4- nitro -5- phenyl-pyrrolidin -2- formic acid
Ester
In a nitrogen atmosphere, silver acetate (CAS# 563-63-3,172mg, 1.0mmol, 0.15 equivalent) is added to (S)-
2- { [1- phenyl -methyl- (E)-subunit]-amino }-propanoic acid tert-butyl ester (1.6g, 6.9mmol, 1.0 equivalent) and (E) -3,3- diformazan
Base -1- nitro but-1-ene (890mg, 6.9mmol, 1.0 equivalent) is in the solution in acetonitrile.Addition triethylamine (960 μ L,
6.9mmol, 1.0 equivalents), and reaction mixture is stirred at room temperature 18 hours.Solvent is evaporated, and residue is dissolved in two
It filters in chloromethanes and over celite.Filtrate water is washed, and combined organic layer is dried over sodium sulfate, filter and
It is concentrated in vacuum.Crude mixture is purified by flashchromatography on silica gel (heptane/ethyl acetate 100/0 to 80/20), to mention
For title compound (350mg, 14%).LC/MS(ESI+)m/z 363.4(M+H)+。
Core 56
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (2- methoxy propane -2- base) -4- nitro -5- Phenylpyrrolidine -
2- formic acid esters
The 1.5M solution of lithium bromide (14.25mL, 21.38mmol) is added to (E)-tert-butyl 2- (benzylideneamino) second
Acid esters (core 1A, 3.0g, 12.72mmol) in the solution in anhydrous tetrahydro furan (46mL), and by gained mixture with dry ice/
Acetone bath is cooling.Then be slowly added (E)-3- methoxyl group-3- methyl-1-nitro but-1-ene (core 36D, 1.847g,
2,3,4,6,7,8,9,10- octahydro pyrimidos [1,2- are then added dropwise in the 12.72mmol) solution in tetrahydrofuran (4.9mL)
A] azepine(2.56mL, 16.99mmol).After stirring reaction mixture one hour near -78 DEG C, by dry ice from bath
It takes out and bath is made within 60 minutes to be warmed to -15 DEG C, be then warmed to 0 DEG C through 60 minutes again.Cryostat is removed, by reaction mixture
It is stirred at room temperature 15 minutes.Addition is saturated aqueous NH4Cl (50mL) is rinsed with methyl tertiary butyl ether(MTBE) (50mL).Two-phase is mixed
It closes object and thoroughly stirs and then diluted with salt water (50mL).It is extracted twice, and will merge by aqueous phase separation and with methyl tertiary butyl ether(MTBE)
Organic phase be washed with brine, dry (Na2SO4), and be concentrated to obtain residue, residue 40mL heptane is ground simultaneously
It stores 16 hours at ambient temperature.Obtained solid is filtered.Filtrate is concentrated and is loaded on 12g column, with 0-60% acetic acid
Ethyl ester/heptane gradient elution 20 minutes merges with filtered solid to racemic-(2R, 3S, 4R, 5R)-tert-butyl
3- (2- methoxy propane -2- base) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (2.45g, 6.72mmol, 52.8%
Rate).1H NMR (501MHz, chloroform-d) δ ppm 7.40-7.29 (m, 5H), 5.36 (dd, J=6.0,2.2Hz, 1H), 4.58
(s, 1H), 3.96 (d, J=6.6Hz, 1H), 3.27 (s, 3H), 3.04 (dd, J=6.7,2.2Hz, 1H), 1.57 (s, 9H),
1.35 (s, 3H), 1.31 (s, 3H)；MS(ESI+)m/z 365(M+H)+。
Core 57
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2,2- dimethyl -2,3- Dihydrobenzofuranes -7- base) -4-
Nitro-pyrrole alkane -2- formic acid esters
Core 57A
(E)-ethyl 2- (((2,2- dimethyl -2,3- Dihydrobenzofuranes -7- base) methylene) amino) acetic acid esters
By ethyl 2- amion acetic acid ester hydrochloride [CAS# 623-33-6] (4.95g, 35.5mmol) and magnesium sulfate
(6.83g, 56.7mmol) is suspended in methylene chloride (47mL), and is handled with triethylamine (4.94mL, 35.5mmol).It will mixing
Object is stirred at room temperature 1 hour, adds 2,2- dimethyl -2,3- Dihydrobenzofuranes -7- formaldehyde [CAS# 38002-88-9]
(5g, 28.4mmol), and mixture is stirred at room temperature overnight.Solid material is removed via filtering, and by filtrate water
It with salt water washing, is dried over sodium sulfate, filters and be concentrated to provide title compound, be directly used in next step.1H
NMR (400MHz, chloroform-d) δ ppm 8.53 (d, J=15Hz, 1H), 7.78 (dd, J=8.0,1.2Hz, 1H), 7.19 (dq, J
=7.2,1.3Hz, 1H), 6.84 (t, J=7.4Hz, 1H), 4.39 (d, J=1.3Hz, 2H), 4.23 (q, J=7.1Hz, 2H),
3.01 (t, J=1.1Hz, 2H), 1.50 (s, 6H), 1.30 (t, J=7.1Hz, 3H)；MS(DCI+)m/z 262(M+H)+。
Core 57B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2,2- dimethyl -2,3- Dihydrobenzofuranes -7- base) -4-
Nitro-pyrrole alkane -2- formic acid esters
By (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2,2- dimethyl -2,3- Dihydrobenzofuranes -7- base) -
4- nitro-pyrrole alkane -2- formic acid esters (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- bis-
Hydrogen oxazole -2- base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.278g, 0.369mmol) and trifluoro
Copper methane sulfonate (I) dimer benzene complex (0.071g, 0.142mmol) is dissolved in tetrahydrofuran (73mL).By mixture N2
Stream injection 4 hours.Gained mixture is stirred at room temperature 1.5 hours, and is cooled to 5 DEG C of < in ice-water bath.Addition is four
Example 57A (7.41g, 28.4mmol) in hydrogen furans (5mL).Dropwise addition 2- methyl propyl- 2- potassium alcoholate (0.284mL,
0.284mmol), it and through 25 minutes pure (E) -3,3- dimethyl -1- nitro but-1-enes (3.66g, 28.4mmol) of addition, protects
Hold 10 DEG C of internal temperature <.After the completion of addition, mixture is stirred at the same temperature 15 minutes.By reaction mixture methyl
Tertbutyl ether (200mL) and aqueous ammonium chloride (100mL) dilution of saturation, and be stirred at room temperature 15 minutes.Organic layer is used full
It with aqueous sodium bicarbonate and salt water washing, is dried over sodium sulfate, filters and is concentrated.Rough material is purified via chromatography,
The 0-25% ethyl acetate elution being used on 220g silicagel column in heptane, to provide title compound.1H NMR (501MHz, chlorine
Imitative-d) δ ppm 7.07 (ddt, J=16.1,7.7,1.1Hz, 2H), 6.82 (t, J=7.6Hz, 1H), 5.31 (dd, J=5.7,
2.4Hz, 1H), 4.44 (dd, J=13.4,5.7Hz, 1H), 4.33 (qd, J=7.1,1.6Hz, 2H), 3.81 (dd, J=10.3,
7.2Hz, 1H), 3.51 (dd, J=13.4,10.5Hz, 1H), 3.02 (q, J=1.1Hz, 2H), 2.89 (dd, J=7.2,
2.3Hz, 1H), 1.51 (d, J=2.7Hz, 6H), 1.37 (t, J=7.2Hz, 3H), 1.08 (s, 9H)；MS(ESI+)m/z 391
(M+H)+。
Core 58
(2S, 3R, 4S, 5S)-ethyl 5- (benzofuran -7- base) -3- (tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters
Core 58A
(E)-ethyl 2- ((benzofuran -7- methylene) amino) acetic acid esters
Ethyl 2- amion acetic acid ester hydrochloride (1.089g, 7.80mmol) and magnesium sulfate (1.502g, 12.48mmol) is outstanding
Float in methylene chloride (10.40mL), and suspension is handled with triethylamine (1.087mL, 7.80mmol).By mixture in room
Temperature lower stirring 1 hour.Add benzofuran -7- formaldehyde (0.94g, 6.24mmol) in 1mL methylene chloride, and by mixture
It is stirred at room temperature 20 hours.Solid material is removed via filtering, and filtrate water (quick wash is twice) and salt are washed
It washs, is dried over sodium sulfate, filter and be concentrated to provide title compound.1H NMR (400MHz, DMSO-d6) δ ppm 8.80 (d, J
=1.5Hz, 1H), 8.08 (d, J=2.2Hz, 1H), 7.77 (ddd, J=12.1,7.6,1.2Hz, 2H), 7.33 (t, J=
7.6Hz, 1H), 7.03 (d, J=2.2Hz, 1H), 4.50 (d, J=1.3Hz, 2H), 4.13 (q, J=7.1Hz, 2H), 1.21 (t,
J=7.1Hz, 3H)；MS(ESI+)m/z 232.2(M+H)+。
Core 58B
(2S, 3R, 4S, 5S)-ethyl 5- (benzofuran -7- base) -3- (tert-butyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.061g, 0.081mmol) and copper trifluoromethanesulfcomposite
(I) dimer benzene complex (0.016g, 0.031mmol), which is dissolved in, has used N2Stream sprays 4 hours tetrahydrofurans (15.97mL)
In.Gained mixture is stirred at room temperature 1.5 hours, and is added after being cooled to 5 DEG C of < in ice-water bath in tetrahydrofuran
(E)-ethyl 2- ((benzofuran -7- methylene) amino) acetic acid esters (1.44g, 6.23mmol) in (1mL).2- first is added dropwise
Base propan-2-ol potassium (0.062mL, 0.062mmol), then through 25 minutes pure (E) -3,3- dimethyl -1- nitro butyl- 1- of addition
Alkene (0.804g, 6.23mmol) is kept for 10 DEG C of internal temperature <.After the completion of addition, mixture is stirred 15 at the same temperature
Minute.Mixture is diluted with methyl tertiary butyl ether(MTBE) (30mL), and is stirred together with the aqueous ammonium chloride of 30mL saturation at room temperature
15 minutes.By organic layer saturation aqueous sodium bicarbonate and salt water washing, it is dried over sodium sulfate and filters.Filtrate is concentrated, and
Residue is purified by flash chromatography (0 to 30% ethyl acetate in heptane), to provide title compound.1H NMR
(400MHz, chloroform-d) δ ppm 7.68 (d, J=2.2Hz, 1H), 7.58 (dd, J=7.0,1.9Hz, 1H), 7.27 (dd, J=
9.4,7.1Hz, 2H), 6.82 (d, J=2.2Hz, 1H), 5.46 (dd, J=5.7,2.3Hz, 1H), 4.90 (dd, J=12.0,
5.7Hz, 1H), 4.36 (qd, J=7.2,1.3Hz, 2H), 3.91 (t, J=7.8Hz, 1H), 3.64 (d, J=11.1Hz, 1H),
2.98 (dd, J=7.0,2.3Hz, 1H), 1.38 (t, J=7.1Hz, 3H), 1.14 (s, 9H)；MS(ESI+)m/z 361.1(M+
H)+。
Example 1
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl)
Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid
Example 1A
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- phenyl pyrazoline
Cough up alkane -2- formic acid esters
At 0 DEG C, by racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -
2- formic acid esters (core 1,2.0g, 5.74mmol) and triethylamine (1.203mL, 8.61mmol) are in CH2Cl2Solution in (20mL) is used
Cyclohexanecarbonyl chloride (0.998mL, 7.46mmol) processing, stirs 30 minutes at 0 DEG C and is stirred at room temperature 1 hour.Addition
CH2Cl2(20mL).Mixture is saturated aqueous NaHCO3With salt water washing, through MgSO4It dries, filters, is concentrated and in 25g silicon
Chromatography is carried out in rubber column gel column, the elution of 0-60% ethyl acetate in heptane, with provide title compound (1.6g, 3.49mmol,
60.8% yield), it is used without further purification.LC/MS(APCI+)m/z 403.3(M+H)+。
Example 1B
Racemic-(2R, 3R, 4R, 5R)-tert-butyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- phenyl pyrazoline
Cough up alkane -2- formic acid esters
By racemic-(2R, 3S, 4R, 5R)-tert-butyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- phenyl
Pyrrolidines -2- formic acid esters (example 1A, 1.04g, 2.268mmol) is in acetic acid (11.68mL, 204mmol) and ethyl acetate
Solution in (66.6mL, 680mmol) is handled with zinc (2.224g, 34.0mmol), and is stirred 1 hour at 55 DEG C, cooling, uses second
Acetoacetic ester is diluted and is filtered to remove solid.It concentrates the filtrate to dry.Residue in ethyl acetate and is saturated aqueous NaHCO3
Between distribute.Ethyl acetate layer is washed with brine, through MgSO4It is dried, filtered and concentrated.Via quick on 24g silicagel column
The purifying (ethyl acetate/methanol (9: 1) in heptane) that chromatography carries out provides title compound 0.95g, and (98% obtains
Rate).1HNMR (400MHz, chloroform-d) δ ppm 7.65-7.54 (m, 2H), 7.40 (q, J=7.1Hz, 2H), 7.33-7.29 (m,
1H), 4.99 (d, J=6.6Hz, 1H), 4.44 (d, J=3.3Hz, 1H), 3.57 (dd, J=6.7,2.4Hz, 1H), 2.09-
1.99 (m, 2H), 1.51 (s, 9H), 1.56-1.51 (m, 2H), 1.50-1.41 (m, 3H), 1.23-1.13 (m, 3H), 1.09
(dt, J=12.8,3.4Hz, 2H), 1.04 (s, 9H), 0.98 (dt, J=12.8,3.3Hz, 1H), 0.54 (qt, J=12.8,
4.1Hz, 1H)；MS(ESI+)m/z 429.0(M+H)+。
Example 1C
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((6- methyl -4- (fluoroform
Base) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formic acid
By chloro- 6- methyl -4- (trifluoromethyl) pyridine (CAS#52334-81-3,183mg, 0.933mmol) of 2-, example 1A
The mixture of (200mg, 0.467mmol) and potassium carbonate (193mg, 1.400mmol) in n,N-Dimethylformamide (0.5mL)
It is sealed in microwave vial, and is stirred 2 hours at 140 DEG C.Mixture is cooling, filtering, and solid is washed with methanol.It will filter
Liquid concentration, is dissolved in trifluoroacetic acid (0.5mL), and be stirred overnight at ambient temperature.By reaction mixture directly via HPLC
It is purified using trifluoroacetic acid method, to provide title compound 78mg (31.4% yield).1HNMR (400MHz, chloroform-d) δ
Ppm 7.17 (d, J=4.5Hz, 6H), 6.48 (s, 1H), 6.20 (s, 1H), 5.45 (d, J=7.4Hz, 1H), 5.17 (s, 1H),
4.76 (d, J=4.0Hz, 1H), 2.76 (s, 1H), 2.43 (s, 3H), 2.23 (t, J=10.9Hz, 1H), 1.76 (d, J=
10.3Hz, 2H), 1.46 (d, J=12.7Hz, 2H), 1.12 (d, J=13.2Hz, 4H), 1.07 (s, 9H), 0.96 (d, J=
13.1Hz, 1H), 0.68 (d, J=13.0Hz, 1H)；MS(ESI-)m/z 530(M-H)-。
Example 2
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methoxyl group -4- (fluoroform
Base) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid
Example 2A
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- phenylpyrrole
Alkane -2- formic acid esters
Core 1 (4.3666g, 13.63mmol) is dissolved in methylene chloride (34.1mL), and add triethylamine (3.80mL,
27.3mmol), cyclohexanecarbonyl chloride (1.668mL, 13.77mmol) then is added at 0 DEG C, while cooling in ice-water bath.
Reaction mixture is stirred 15 minutes at the same temperature, then warmed to room temperature, its completion is shown by LC-MS at this time.It will
Reaction mixture is diluted with methylene chloride (30mL), and is washed with the aqueous HCl of the 1M of 3x50mL and salt water (30mL).By organic layer
It is dried over sodium sulfate, filters and is concentrated.Residue heptane (40mL) is ground to provide the title compound of 5.66g.1HNMR
400MHz, dimethyl sulfoxide-d6) δ ppm 7.58 (d, J=7.1Hz, 2H), 7.27 (qd, J=7.6,6.3,3.6Hz, 3H),
5.76-5.53 (m, 2H), 4.70 (d, J=3.7Hz, 1H), 4.24 (q, J=7.0Hz, 2H), 3.01 (t, J=3.4Hz, 1H),
2.19 (s, 1H), 1.69 (d, J=14.7Hz, 2H), 1.50 (d, J=9.8Hz, 2H), 1.28 (t, J=7.1Hz, 3H), 1.26-
1.06 (m, 6H), 1.01 (s, 9H)；MS(ESI+)m/z 431.2(M+H)+。
Example 2B
Racemic-(2R, 3R, 4R, 5R)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- phenylpyrrole
Alkane -2- formic acid esters
By example 2A (10.71g, 24.88mmol) be dissolved in ethyl acetate (731mL, 7463mmol) and acetic acid (128mL,
In mixture 2239mmol).It adds zinc (24.40g, 373mmol), and gained suspension is heated to 55 DEG C and continues 90 points
Clock.Flask is cooled to environment temperature, solid material is removed by sinter funnel via filtering, and filtrate is dense in a vacuum
Contracting.Gained residue is distributed between saturation aqueous sodium bicarbonate and ethyl acetate.Organic extract is dried over sodium sulfate,
It filters and is concentrated in a vacuum to provide thick solid, by the thick solid via purified by flash chromatography, used on 120g silicagel column
20: 80 to 100: 0 ethyl acetate: heptane elutes 20 minutes, to provide the title compound of 9.31g.1HNMR (400MHz, two
Methyl sulfoxide-d6) δ ppm 7.75-7.49 (m, 2H), 7.29 (dt, J=36.0,7.4Hz, 3H), 5.05 (d, J=7.1Hz,
1H), 4.39 (d, J=4.2Hz, 1H), 4.24-4.09 (m, 2H), 3.67 (dd, J=7.2,4.0Hz, 1H), 2.16 (s, 1H),
2.03 (t, J=4.0Hz, 1H), 1.74-1.54 (m, 2H), 1.46 (s, 2H), 1.30-1.02 (m, 6H), 1.22 (t, J=
8.0Hz, 3H), 0.99 (s, 9H).MS(ESI+)m/z 401.3(M+H)+。
Example 2C
Racemic-(2R, 3R, 4R, 5R)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- ((6- methoxyl group -4- (three
Methyl fluoride) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formic acid esters
By example 2B (300mg, 0.686mmol), cesium carbonate (671mg, 2.059mmol), 4,5- bis- (diphenylphosphinos)-
9,9- dimethylxanthenes (Xantphos) (79mg, 0.137mmol) and Pd2dba3(tris(dibenzylideneacetone) dipalladium (0),
62.9mg, 0.069mmol) it is weighed in microwave vial.It adds dimethylbenzene (1961 μ L), then adds the chloro- 6- methoxyl group -4- of 2-
(trifluoromethyl) pyridine (290mg, 1.373mmol), and by gained suspension N2Injection 5 minutes.Bottle is sealed and added
It is heated to 140 DEG C in heat block and continues 16 hours.Mixture is cooled to environment temperature, simultaneously with methyl tertiary butyl ether(MTBE) (10mL) dilution
It is filtered by syringe type filter.By filtrate be concentrated and via purified by flash chromatography, on 40g silicagel column with 0: 100 to
20: 80 ethyl acetate: heptane elutes 20 minutes, to provide the title compound of 190mg.1HNMR (400MHz, chloroform-d) δ
Ppm 7.58-7.46 (m, 2H), 7.35-7.20 (m, 4H), 6.12 (s, 1H), 5.72 (s, 1H), 5.22-5.13 (m, 2H),
4.45 (d, J=6.6Hz, 1H), 4.37 (s, 1H), 4.29 (q, J=7.1Hz, 2H), 3.89 (s, 2H), 2.23 (t, J=
6.4Hz, 1H), 2.07 (ddd, J=11.6,8.4,3.3Hz, 1H), 1.79-1.55 (m, 5H), 1.52-1.37 (m, 5H), 1.35
(t, J=7.2Hz, 3H), 1.06 (s, 9H)；MS(ESI+)m/z 576.4(M+H)+。
Example 2D
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methoxyl group -4- (fluoroform
Base) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid
Example 2C (32mg, 0.056mmol) is dissolved in tetrahydrofuran (278 μ L), and add aqueous lithium (1M,
167 μ l, 0.167mmol).Gained mixture is vigorously stirred 48 hours, is acidified to pH by adding the aqueous HCl of 1M at this time
=3.Entire mixture is loaded on 4g silicagel column, and with 0: 100 to 50: 50 ethyl acetate: heptane elutes 15 minutes, with
Provide the title compound of 18mg.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.44 (d, J=6.8Hz, 2H), 7.22-
7.07 (m, 3H), 6.04 (d, J=9.4Hz, 1H), 5.98 (d, J=6.6Hz, 2H), 5.33 (d, J=8.2Hz, 1H), 4.99
(dt, J=9.4,8.0Hz, 1H), 4.38 (d, J=6.1Hz, 1H), 3.87 (s, 3H), 2.41 (t, J=6.7Hz, 1H), 2.23
(s, 1H), 1.68 (d, J=14.1Hz, 2H), 1.47 (s, 2H), 1.35-1.04 (m, 6H), 1.02 (s, 9H)；MS(ESI+)m/z
548.2(M+H)+。
Example 3
(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -2-
Base] amino } -5- Phenylpyrrolidine -2- formic acid
Example 3A
Racemic-(2R, 3R, 4R, 5R)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- ((6- methyl -4- (trifluoro
Methyl) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formic acid esters
By bis- (diphenylphosphino) -9,9- dimethylxanthenes (Xantphos) of example 2B (240mg, 0.429mmol), 4,5-
(0.144g, 0.250mmol), cesium carbonate (2.440g, 7.49mmol) and acid chloride (II) (0.028g, 0.125mmol) weigh
Into 50-mL round-bottomed flask.By flask N2Stream purging, and the toluene (25mL) sprayed with nitrogen stream 1 hour is added, so
Chloro- 6- methyl -4- (trifluoromethyl) pyridine (0.523mL, 3.74mmol) of 2- is added afterwards.At ambient temperature by gained suspension
Stirring 5 minutes.Flask is heated to 100 DEG C of internal temperature in heating mantle, and continues heating 16 hours at the same temperature.
Flask is cooled to environment temperature, and solid material is removed using sinter funnel via filtering.Filtrate is concentrated and in 40g silicon
Via purified by flash chromatography in rubber column gel column, with 0: 100 to 30: 70 ethyl acetate: heptane elutes 15 minutes, then with 30: 70 to
100: 0 ethyl acetate: heptane elutes 5 minutes, to provide the title compound of 260mg.1HNMR (400MHz, dimethyl sulfoxide-
d6) δ ppm 7.45 (d, J=7.3Hz, 2H), 7.29-7.08 (m, 3H), 6.50 (s, 1H), 6.26 (s, 1H), 5.85 (s, 1H),
5.33 (d, J=8.3Hz, 1H), 4.99 (q, J=8.4Hz, 1H), 4.37 (d, J=6.8Hz, 1H), 4.18 (q, J=7.0Hz,
2H), 2.39 (t, J=7.4Hz, 1H), 2.35 (s, 3H), 2.19 (s, 1H), 1.67 (d, J=12.1Hz, 2H), 1.45 (t, J=
14.4Hz, 2H), 1.31 (d, J=12.1Hz, 1H), 1.24 (t, J=7.0Hz, 3H), 1.17-1.03 (m, 4H), 1.00 (s,
9H)；MS(ESI+)m/z 560.4(M+H)+。
Example 3B
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- ((6- methyl -4- (trifluoromethyl) pyrrole
Pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formic acid esters
With
Example 3C
(2R, 3R, 4R, 5R)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- ((6- methyl -4- (trifluoromethyl) pyrrole
Pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formic acid esters
Example 3A (3.67g) is separated via preparative chirality SFC chromatography, using column WHELK-O S.S, column dimension:
21x250mm, 5 microns, sequence number: 780103, CO2Flow velocity is 68g/ minutes, and the concentration of methanol and cosolvent isopropanol is
52.8mg/mL, to provide 615mg example 3B (room temperature=8.4 minute) and 760mg example 3C (room temperature=6.4 minute).Analyze number
According to (1H NMR and MS) it is identical as being reported for example 3A.
Example 3D
(2R, 3R, 4R, 5R) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((6- methyl -4- (trifluoromethyl) pyridine -
2- yl) amino) -5- Phenylpyrrolidine -2- formic acid
Example 3C (615mg, 1.099mmol) is dissolved in 6.5mL tetrahydrofuran, 3.3mL water and 1.1mL methanol.Addition
Lithium hydroxide monohydrate (461mg, 10.99mmol), and reaction mixture is vigorously stirred at ambient temperature 2 hours.It will be anti-
It answers mixture to be acidified to pH=3 with the aqueous HCl of 1M, and the mixture methylene chloride of 3x10mL is extracted.By the organic of merging
Extract is washed with salt water (10mL), is dried over sodium sulfate, and is filtered and is concentrated to provide title compound (446mg).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.44 (d, J=7.4Hz, 2H), 7.14 (dt, J=13.9,6.8Hz, 3H), 6.49
(s, 1H), 6.22 (s, 1H), 5.84 (d, J=9.0Hz, 1H), 5.34 (d, J=8.2Hz, 1H), 4.98 (q, J=8.0Hz,
1H), 4.39 (d, J=5.9Hz, 1H), 2.40 (t, J=6.4Hz, 1H), 2.34 (s, 3H), 2.24 (s, 2H), 1.69 (d, J=
13.1Hz, 2H), 1.48 (d, J=8.4Hz, 2H), 1.28 (d, J=16.8Hz, 2H), 1.26-1.12 (m, 4H), 1.02 (s,
9H)；MS(ESI+)m/z 532.4(M+H)+；Optical activity data: [α]D 23=+97.2 (c=1, methanol).
Example 4
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -2-
Base] amino } -5- Phenylpyrrolidine -2- formic acid
Example 3B (760mg, 1.358mmol) is dissolved in 8.1mL tetrahydrofuran, 4.1mL water and 1.3mL methanol.Addition
Lithium hydroxide monohydrate (570mg, 13.58mmol), and reaction mixture is vigorously stirred at ambient temperature 3 hours.It will mix
It closes object and is acidified to pH=3 with the aqueous HCl of 1M, and extracted with the methylene chloride of 3x15mL.By combined extract salt water
(10mL) washing, is dried over sodium sulfate, filters and be concentrated to provide the title compound of 556mg.1HNMR (400MHz, dimethyl
Sulfoxide-d6) δ ppm 7.44 (d, J=7.4Hz, 2H), 7.14 (dt, J=13.9,6.8Hz, 3H), 6.49 (s, 1H), 6.22 (s,
1H), 5.84 (d, J=9.0Hz, 1H), 5.34 (d, J=8.2Hz, 1H), 4.98 (q, J=8.0Hz, 1H), 4.39 (d, J=
5.9Hz, 1H), 2.40 (t, J=6.4Hz, 1H), 2.34 (s, 3H), 2.24 (s, 2H), 1.69 (d, J=13.1Hz, 2H), 1.48
(d, J=8.4Hz, 2H), 1.28 (d, J=16.8Hz, 2H), 1.26-1.12 (m, 4H), 1.02 (s, 9H)；MS(ESI+)m/z
532.4(M+H)+；Optical activity data.[α]D 23=-93.8 (c=1, methanol).
Example 5
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- { [6- methyl -
4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid
Example 5A
Racemic-(2R, 3S, 4R, 5R)-tert-butyl 1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- nitre
Base -5- Phenylpyrrolidine -2- formic acid esters
At 25 DEG C, by core 56 (1.7g, 4.66mmol) and triethylamine (1.300mL, 9.33mmol) in methylene chloride
Solution in (21.20mL) is handled dropwise with cyclohexanecarbonyl chloride (0.780mL, 5.83mmol), is stirred 2 hours, is used methyl- tert
Butyl ether (20mL) dilution is saturated aqueous NaHCO with washing3(5mL) and 1N NH4The washing of OH (1mL) aqueous solution, it is dry through sodium sulphate
It is dry, it filters and is concentrated to provide residue.Mixture is ground with 100mL heptane and is placed 16 hours at ambient temperature.It will
Mixture is filtered to provide raw sediment (2.01g).Rough material is dissolved in 3mL methylene chloride and is loaded on 40g column, 0- is used
The gradient elution of 70% ethyl acetate/heptane 20 minutes, to provide desired product racemic-(2R, 3S, 4R, 5R)-tertiary fourth
Base 1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters 1980-2
(1.56g, 3.29mmol, 70.5% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.55 (d, J=6.9Hz,
2H), 7.31-7.17 (m, 3H), 5.61 (d, J=3.0Hz, 2H), 4.62 (d, J=3.9Hz, 1H), 3.26 (dd, J=4.0,
2.6Hz 1H), 3.15 (s, 3H), 2.16 (s, 1H), 1.67 (s, 2H), 1.51 (s, 10H), 1.22 (d, J=6.0Hz, 10H),
1.08 (t, J=10.0Hz, 2H), 0.84 (d, J=7.6Hz, 1H)；MS(ESI+)m/z 475(M+H)+。
Example 5B
Racemic-(2R, 3R, 4R, 5R)-tert-butyl 4- amino -1- (cyclohexane carbo) -3- (2- methoxy propane -2-
Base) -5- Phenylpyrrolidine -2- formic acid esters
Example 5A (1.56g, 3.29mmol) and tetrahydrofuran (47.0mL) are added in 250mL SS pressure bottleIn 2800 aqueous slurry of nickel (4g, 30.7mmol), and mixture is vibrated 16 hours at 50psi and environment temperature.It will
Reaction filters and removes solvent in a vacuum, to give racemic-(2R, 3R, 4R, 5R)-tert-butyl 4- amino -1- (hexamethylene
Alkyl carbonyl) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid esters (1.45g, 3.26mmol, 99% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.56 (bs, 2H), 7.31 (t, J=7.5Hz, 2H), 7.22 (t, J=
7.4Hz, 1H), 5.02 (d, J=7.3Hz, 1H), 4.33 (d, J=4.7Hz, 1H), 3.65 (dd, J=7.3,4.6Hz, 1H),
3.13 (s, 3H), 2.32 (s, 1H), 2.15 (d, J=12.9Hz, 1H), 1.62 (d, J=10.2Hz, 2H), 1.46 (s, 10H),
1.30-1.10 (m, 2H), 1.21 (s, 3H), 1.19 (s, 3H), 1.05 (m, 2H), 0.82 (bs, 2H)；MS(ESI+)m/z 445
(M+H)+。
Example 5C
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ((6- methyl -
4- (trifluoromethyl) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formic acid
Example 5B (100mg, 0.225mmol), Pd are packed into 4mL bottle2(dba)3(tris(dibenzylideneacetone) dipalladium
(0), 4.12mg, 0.00450mmol), 4- (di-t-butyl phosphino-)-n,N-Dimethylaniline (2.77mg, 0.00990mmol)
With cesium carbonate (147mg, 0.450mmol).Mixture nitrogen is purged 15 minutes, and adds the chloro- 6- methyl-of 2- into bottle
4- (trifluoromethyl) pyridine (48.4mg, 0.247mmol) is in the anhydrous dioxanes (0.9mL) for purging 15 minutes with nitrogen
Solution.Reaction mixture is 16 hours heating and continuous at 80 DEG C.Mixture is filtered, and filtrate is concentrated.Rough material is led to
Flash chromatography (12g column, gradient was 0%-70% ethyl acetate/heptane, through 20 minutes) purifying is crossed, to provide the thick tert-butyl ester
(43mg) uses it trifluoroacetic acid (0.4mL) to handle 2 hours at ambient temperature.Mixture is concentrated, and residue is passed through
RP chromatography is purified using trifluoroacetic acid method, with acquisition (2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- first
Oxygroup propane -2- base) -4- ((6- methyl -4- (trifluoromethyl) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- methanoic acid trifluoro
Acetate (31mg, 0.047mmol, 20.83% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.42 (d, J=
7.3Hz, 2H), 7.14 (dt, J=12.4,6.7Hz, 2H), 6.51 (s, 1H), 6.27 (s, 1H), 5.84 (s, 1H), 5.36 (d, J
=8.2Hz, 1H), 4.95 (d, J=7.8Hz, 1H), 4.49 (d, J=6.2Hz, 1H), 3.13 (s, 3H), 2.68 (t, J=
6.7Hz, 1H), 2.34 (s, 3H), 2.22 (s, 1H), 1.68 (d, J=13.5Hz, 2H), 1.47 (bs, 2H), 1.30 (t, J=
11.1Hz, 1H), 1.22 (d, J=1.3Hz, 6H), 1.12 (d, J=22.9Hz, 3H), 0.73 (bs, 1H)；MS(ESI+)m/z
548(M+H)+。
Example 6
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
To 2- methoxyl group -5- (trifluoromethyl) benzaldehyde (38.6mg, 0.189mmol), example 5B (70mg,
0.157mmol) and zinc chloride (II) (21.46mg, 0.157mmol) be in methanol sodium acetate/acetate buffer (pH=4,
Sodium cyanoborohydride (14.8mg, 0.236mmol) is added in solution in 1mL), and it is small to react stirring 2 at ambient temperature
When.Solvent is removed, and gained residue is subjected to chromatography using 12g silicagel column, with the gradient of 0-80% ethyl acetate/heptane
Elution 20 minutes, to provide residue (76mg), is dissolved in trifluoroacetic acid (0.5mL).Solvent is removed, and by rough material
It is purified by RP chromatography using trifluoroacetic acid method, to obtain racemic-(2R, 3R, 4R, 5R) -1- (hexamethylene carbonyl
Base) -4- ((2- methoxyl group -5- (trifluoromethyl) benzyl) amino) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2-
Methanoic acid trifluoro acetate (64mg, 0.093mmol, 58.9% yield).1H NMR (400MHz, dimethyl sulfoxide-d6)δppm
7.57 (s, 2H), 7.52 (dd, J=9.1,2.3Hz, 1H), 7.37-7.24 (m, 4H), 7.05 (d, J=8.6Hz, 1H), 5.28
(d, J=7.2Hz, 1H), 4.50 (d, J=3.6Hz, 1H), 3.69 (m, 4H), 3.65 (bs, 2H), 3.52 (d, J=14.0Hz,
1H), 2.70 (s, 1H), 2.28 (m, 1H), 1.65 (d, J=9.3Hz, 2H), 1.50 (m, 2H), 1.30-1.15 (m, 4H), 1.19
(d, J=6.1Hz, 6H), 1.08 (m, 2H), 0.79 (bs, 1H)；MS(ESI+)m/z 577(M+H)+。
Example 7
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid
Example 7A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- Phenylpyrrolidine -2- first
Acid esters
By ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (core 7,
2.00g, 6.24mmol) it is dissolved in methylene chloride (25mL), and triethylamine (1.75mL, 12.56mmol) is added, then add ring
Hexane phosgene (1.01g, 6.89mmol).Reaction is stirred 14 hours at ambient temperature.By reaction methylene chloride
(50mL) dilution, and with the aqueous HCl of 1M (2x50mL)
With salt water washing.Organic layer is dried over sodium sulfate, filter and be concentrated with provide title compound (2.68g,
100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.57 (d, J=7.1Hz, 2H), 7.31-7.19 (m,
3H), 5.71-5.57 (m, 2H), 4.69 (d, J=3.7Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 3.00 (t, J=3.4Hz,
1H), 2.26-2.09 (m, 1H), 1.74-1.59 (m, 2H), 1.49 (d, J=8.7Hz, 2H), 1.32-1.14 (m, 7H), 1.07
(t, J=9.5Hz, 2H), 1.00 (s, 9H)；MS(ESI+)m/z 431(M+H)+。
Example 7B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- first
Acid esters
Example 7A (1.23g, 2.86mmol) and tetrahydrofuran (30mL) are added in 250mL stainless steel pressure bottleIn 2800 aqueous slurry of nickel (2.54g, 21.64mmol).Mixture is vibrated 16 hours at 50psi and environment temperature.
HPLC monitoring shows that there are both starting materials and product.It adds again2800 aqueous slurry of nickel (2.5g, 19.17mmol),
And vibrate reaction 16 hours at 50psi and environment temperature, HPLC shows that starting material has been consumed at this time.Reaction is filtered
And filtrate is concentrated, to provide title compound (1.13g, 99%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ
Ppm 7.58 (d, J=7.4Hz, 2H), 7.33 (t, J=7.5Hz, 2H), 7.24 (dd, J=8.2,6.3Hz, 1H), 5.04 (d, J
=7.2Hz, 1H), 4.38 (d, J=4.2Hz, 1H), 4.15 (qd, J=7.1,1.2Hz, 2H), 3.66 (dd, J=7.2,
4.0Hz, 1H), 2.16 (d, J=11.7Hz, 1H), 2.03 (d, J=4.4Hz, 1H), 1.67-1.56 (m, 2H), 1.46 (d, J=
9.0Hz, 2H), 1.23 (t, J=7.1Hz, 3H), 1.20-1.11 (m, 4H), 1.05 (t, J=10.7Hz, 2H), 0.99 (s,
9H)；MS(ESI+)m/z 401(M+H)+。
Example 7C
Ethyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- first
Acid esters
By example 7B (54.4mg, 0.136mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (39.8mg,
It 0.207mmol) is dissolved in methanol (1mL), and stirs 1 hour at ambient temperature.Addition sodium cyanoborohydride (43.6mg,
0.694mmol), and by reaction it is stirred at ambient temperature 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filtering
And purified using ammonium acetate method by reverse phase, to provide title compound (50.8mg, 65%).1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.64-7.50 (m, 2H), 7.30 (t, J=7.4Hz, 2H), 7.23 (t, J=7.3Hz,
1H), 7.10 (dd, J=8.5,2.6Hz, 1H), 6.90 (d, J=2.6Hz, 1H), 6.71 (d, J=8.5Hz, 1H), 5.18 (d, J
=6.8Hz, 1H), 4.50 (d, J=2.9Hz, 1H), 4.09 (qd, J=7.1,2.9Hz, 2H), 3.52 (s, 3H), 3.50-3.41
(m, 2H), 3.30 (d, J=13.5Hz, 1H), 2.33 (s, 1H), 2.18 (s, 1H), 1.68-1.58 (m, 2H), 1.54-1.40
(m, 2H), 1.18 (d, J=8.4Hz, 17H), 0.98 (s, 9H)；MS(ESI+)m/z 577(M+H)+。
Example 7D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid
Example 7C (47.8mg, 0.136mmol) is dissolved in methanol (1mL).It adds LiOH (1M, 0.5mL, 0.5mmol)
And reaction is heated to 50 DEG C and is kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, dimethyl sulfoxide is used
(1mL) dilution, is filtered and is purified by RP chromatography using trifluoroacetic acid method, to provide the mark for being in trifluoroacetate
It inscribes compound (45.7mg, 83%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.59-7.50 (m, 2H),
7.37 (t, J=7.5Hz, 2H), 7.29 (t, J=7.3Hz, 1H), 7.21 (dd, J=8.6,2.6Hz, 1H), 7.02 (d, J=
2.5Hz, 1H), 6.79 (d, J=8.6Hz, 1H), 5.31 (d, J=7.0Hz, 1H), 4.51 (d, J=2.1Hz, 1H), 3.77-
3.69 (m, 3H), 3.56 (s, 3H), 3.43 (d, J=13.6Hz, 1H), 2.49 (s, 1H), 2.28 (s, 1H), 1.63 (d, J=
10.0Hz, 2H), 1.51 (s, 2H), 1.21 (d, J=0.6Hz, 14H), 0.99 (s, 9H)；MS(ESI+)m/z 549(M+H)+。
Example 8
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid
By example 7B (82.0mg, 0.205mmol) and 2- methoxyl group -4- (trifluoromethyl) benzaldehyde (80.4mg,
It 0.394mmol) is dissolved in methanol (1mL), and mixture is stirred 3 hours at 25 DEG C.Addition sodium cyanoborohydride (52.8mg,
0.840mmol), and by reaction it is stirred at ambient temperature 3 hours.Mixture is poured into water (10mL) and uses dichloromethane
Alkane (3x5mL) extraction.Combined organic matter is concentrated.Residue is dissolved in methanol, and add LiOH (1M, 1.0mL,
1.0mmol), reaction is heated to 50 DEG C and continues 16 hours.By reaction by addition trifluoroacetic acid (0.2mL) quenching, diformazan is used
Base sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide the mark for being in trifluoroacetate
It inscribes compound (63.5mg, 46%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.61-7.46 (m, 2H),
7.32 (t, J=7.4Hz, 2H), 7.25 (t, J=7.3Hz, 1H), 7.16-7.09 (m, 2H), 7.06 (s, 1H), 5.22 (d, J=
6.9Hz, 1H), 4.48 (d, J=2.4Hz, 1H), 3.64 (s, 3H), 3.60-3.48 (m, 2H), 3.39 (d, J=14.2Hz,
1H), 2.36 (s, 1H), 2.31-2.15 (m, 1H), 1.63 (d, J=9.5Hz, 2H), 1.49 (s, 2H), 1.32-1.03 (m,
6H), 0.97 (s, 9H)；MS(ESI+)m/z 561(M+H)+。
Example 9
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 9A
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -5- (trifluoromethyl)
Benzyl) amino) -5- Phenylpyrrolidine
- 2- formic acid esters
By example 7B (50.2mg, 0.125mmol) and 2- methoxyl group -5- (trifluoromethyl) benzaldehyde (34.7mg,
It 0.170mmol) is dissolved in methanol (1mL), and mixture is stirred at ambient temperature 3 hours.Add sodium cyanoborohydride
(44.5mg, 0.708mmol), and reaction is stirred for 16 hours at ambient temperature.Reaction is dilute with dimethyl sulfoxide (1mL)
It releases, filter and is purified using ammonium acetate method by reverse phase, to provide title compound (42.9mg, 58%).1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.62-7.51 (m, 2H), 7.44 (dd, J=8.6,2.4Hz, 1H),
7.30 (t, J=7.4Hz, 2H), 7.24 (d, J=7.2Hz, 1H), 7.19 (d, J=2.4Hz, 1H), 6.98 (d, J=8.6Hz,
1H), 5.19 (d, J=6.9Hz, 1H), 4.51 (d, J=2.8Hz, 1H), 4.10 (q, J=7.0Hz, 2H), 3.64 (s, 3H),
3.51-3.41 (m, 2H), 3.35 (d, J=14.4Hz, 1H), 2.31 (s, 1H), 2.17 (d, J=10.6Hz, 1H), 1.63 (d, J
=9.7Hz, 2H), 1.47 (s, 2H), 1.17 (t, J=7.0Hz, 9H), 0.97 (s, 9H)；MS(ESI+)m/z 589(M+H)+。
Example 9B
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 9A (39.9mg, 0.068mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in trifluoroacetate
Title compound (32.3mg, 71%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.60-7.53 (m, 2H),
7.50 (dd, J=8.7,2.3Hz, 1H), 7.34 (t, J=7.4Hz, 2H), 7.30-7.23 (m, 2H), 7.03 (d, J=8.6Hz,
1H), 5.27 (d, J=7.0Hz, 1H), 4.49 (d, J=2.3Hz, 1H), 3.65 (d, J=18.6Hz, 5H), 3.40 (d, J=
14.2Hz, 1H), 2.42 (s, 1H), 2.25 (s, 1H), 1.63 (d, J=10.1Hz, 2H), 1.49 (s, 2H), 1.30-1.02 (m,
6H), 0.98 (d, J=0.9Hz, 9H)；MS(ESI+)m/z 561(M+H)+。
Example 10
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 10A
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- phenyl -1- ((S)-tetrahydro -2H- pyrrole
Mutter -2- carbonyl) pyrrolidines -2- formic acid esters
With
Example 10B
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- phenyl -1- ((R)-tetrahydro -2H- pyrrole
Mutter -2- carbonyl) pyrrolidines -2- formic acid esters is to tetrahydro -2H- pyrans -2- formic acid (800mg, 6.15mmol) and a few drop N, N- diformazan
Oxalyl chloride is added dropwise in base formamide in the mixture in methylene chloride (10mL) (5mL, 2M are in methylene chloride).Mixture is existed
Stirred at ambient temperature 1 hour, solvent is evaporated, fresh methylene chloride (5mL) is added and evaporates solvent again.Residue is molten
In methylene chloride (2mL), and it is added dropwise to racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- phenyl pyrazoline
Cough up alkane -2- formic acid esters (core 2,1.9g, 6.15mmol) and triethylamine (1.285mL, 9.22mmol) dichloro cooling in ice bath
In mixture in methane (10mL).After addition, reaction mixture is made to be warmed to environment temperature.It adds methylene chloride (20mL),
And be washed with brine mixture, through MgSO4It is dried, filtered and concentrated.The purifying carried out on 40g silicagel column via chromatography
(ethyl acetate elution) in heptane provides the racemic compound (1.02g, 38.36% yield) of example 10A, as washing
De- the first compound (structure is confirmed by X-ray)；LC/MS(ESI+)m/z 432.90(M+H)+.Have also obtained racemic
Examples of compounds 10B (1.0g, 37.6% yield), the second compound as elution.LC/MS(ESI+)433.31(M+H)+。
Example 10C
Racemic-(2R, 3R, 4R, 5R)-ethyl 4- amino -3- (tert-butyl) -5- phenyl -1- ((R)-tetrahydro -2H- pyrrole
Mutter -2- carbonyl) pyrrolidines -2- formic acid esters will be in example 10B (400mg, 0.925mmol), the tetrahydro furan in pressure bottle (50mL)
It mutters (10mL) and in aqueous slurryThe mixture of nickel 2800 (860mg, 6-59mmol) is under 50psi hydrogen in environment
At a temperature of vibrate 16 hours.Mixture is filtered and washs solid with methanol.Combined organic layer is concentrated to provide title
Compound (345mg, 93% yield).LC/MS(ESI+)m/z 403(M+H)+。
Example 10D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [[2- methoxyl group -4- (trifluoromethyl) phenyl] methylamino] -5- benzene
Base -1- [(2S)-oxinane -2- carbonyl] pyrrolidines -2- formic acid
By 2- methoxyl group -4- (trifluoromethyl) benzaldehyde (51.7mg, 0.253mmol), example 10C (85mg,
0.211mmol) and zinc chloride (II) (2.8mg, 0.02mmol) be in methanol acetic acid/sodium acetate buffer (pH=4,
Mixture in 2mL) stirs 10 minutes at ambient temperature.It adds three sodium borohydride of cyano (19.90mg, 0.317mmol), and
Mixture is stirred for 2 hours.Mixture is diluted with methylene chloride (20mL), and is washed with brine, through MgSO4It is dry, mistake
It filters and is concentrated.Carry out on 12g silicagel column via chromatography purifying (ethyl acetate/methanol (10: 1) in heptane with
The gradient elution of 0-50%) racemate (65mg, 54.7% yield) is provided.The ester is dissolved in methanol (2mL) and 4M is aqueous
In LiOH (0.5mL), and stirred 3 hours at 50 DEG C.The pH of mixture is adjusted to 1-2 by addition 2M aqueous HCl.By this two
Kind of enantiomter separate via chiral SFC (instrument: Aurora-1, column:IC, 5%-30% methanol: CO2, 10 points
Clock@3mL/ minutes, 150 bars.First compound of elution is (2R, 3R, 4R, 5R) -3- (tert-butyl) -4- ((2- methoxyl group -4-
(trifluoromethyl) benzyl) amino) -5- phenyl -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid, 25.5mg
(42.5% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.57 (d, J=7.4Hz, 2H), 7.32 (t, J=
7.4Hz, 2H), 7.25 (t, J=7.2Hz, 1H), 7.09 (d, J=2.0Hz, 2H), 7.05 (s, 1H), 5.36 (s, 1H), 4.50
(d, J=2.5Hz, 1H), 3.77 (d, J=11.3Hz, 1H), 3.64 (s, 3H), 3.49-3.31 (m, 5H), 2.64 (d, 5H),
2.28 (t, J=2.5Hz, J=2.4Hz, 1H), 1.58 (dd, J=65.2,12.2Hz, 6H), 0.96 (s, 9H)；MS(ESI+)m/
z 563.3(M+H)+.The second compound of elution is title compound (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((2- methoxy
Base -4- (trifluoromethyl) benzyl) amino) -5- phenyl -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid,
26mg (43.3% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.57 (d, J=7.4Hz, 2H), 7.32 (t, J
=7.4Hz, 2H), 7.25 (t, J=7.2Hz, 1H), 7.10 (t, J=1.3Hz, 2H), 7.05 (s, 1H), 5.36 (s, 1H),
4.50 (d, J=2.5Hz, 1H), 3.77 (d, J=11.5Hz, 1H), 3.64 (s, 3H), 3.52-3.30 (m, 5H), 2.28 (d, J
=2.7Hz, 1H), 1.66 (d, J=12.6Hz, 1H), 1.55-1.31 (m, 4H), 0.96 (s, 9H)；MS(ESI+)m/z 563.2
(M+H)+。
Example 11
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2R*) -2- phenylpropionyl] pyrrolidines -2- formic acid
Example 11A
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- phenyl -1- ((S) -2- phenylpropionyl
Base) pyrrolidines -2- formic acid esters
With
Example 11B
Racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- phenyl -1- ((R) -2- phenylpropionyl
Base) pyrrolidines -2- formic acid esters
To in methylene chloride (4mL) 2- benzenpropanoic acid (1g, 6.66mmol) and one drop n,N-Dimethylformamide in drip
Add oxalyl chloride (4mL, 2M are in methylene chloride).Mixture is stirred 1 hour at ambient temperature, solvent is removed, addition is new
Fresh methylene chloride (2mL), and mixture is concentrated.Residue is dissolved in methylene chloride (2mL), and is added dropwise to racemic-
(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (core 2,1.687mL,
12.11mmol) in the mixture in the methylene chloride in ice bath (10mL).Mixture is stirred 20 minutes in ice bath and is made
It is warmed to environment temperature.It adds methylene chloride (20mL), and mixture is washed with brine, through MgSO4It dries, filters and dense
Contracting.Residue is purified on 40g silicagel column via chromatography, the ethyl acetate in heptane is with 0-40% gradient elution.
First compound of elution is example 11A (610mg, 22.27% yield).LC/MS(APCI+)m/z 453.26(M+H)+.It washes
De- second compound is example 11B (1006mg, 36.7% yield).LC/MS(APCI+)m/z 453.29(M+H)+。
Example 11C
Racemic-(2R, 3R, 4R, 5R)-ethyl 4- amino -3- (tert-butyl) -5- phenyl -1- ((S) -2- phenylpropionyl
Base) pyrrolidines -2- formic acid esters
It will be added in 50mL pressure bottle in the example 11A (600mg, 1.326mmol) in tetrahydrofuran (320mL)In 2800 aqueous slurry of nickel (1.23mg, 9.43 μm of ol).Under 50psi hydrogen, mixture is vibrated 16 at ambient temperature
Hour, and filter.Solid is washed with methanol.Combined solvent is gone divided by providing title racemic compound racemic-
(2R, 3R, 4R, 5R)-ethyl 4- amino -3- (tert-butyl) -5- phenyl -1- ((S) -2- phenylpropionyl) pyrrolidines -2- formic acid
Ester (558mg, 100% yield), purity is sufficient in next step.LC/MS(ESI+)m/z 223(M+H)+。
Example 11D
Racemic-(2R, 3R, 4R, 5R)-ethyl 3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) ammonia
Base) -5- phenyl -1- ((S) -2- phenylpropionyl) pyrrolidines -2- formic acid esters
To 2- methoxyl group -4- (trifluoromethyl) benzaldehyde (53.1mg, 0.260mmol), example 11C (100mg,
0.237mmol) and zinc chloride (II) (32.3mg, 0.237mmol) be in methanol sodium acetate/acetate buffer (pH=4,
Three sodium borohydride of cyano (10.20mg, 0.162mmol) is added in 2mL), and it is small that reaction mixture is stirred to 3 at ambient temperature
When.By solvent in N2Lower removal, and residue is diluted with methylene chloride (10mL), it is washed with brine, through MgSO4It dries, filters
And it is concentrated.Via the purifying of chromatography progress, (ethyl acetate/methanol (10: 1) in heptane is with 0- on 12g silicagel column
50% gradient elution) racemate racemic-(2R, 3R, 4R, 5R)-ethyl 3- (tert-butyl) -4- ((2- methoxyl group-is provided
4- (trifluoromethyl) benzyl) amino) -5- phenyl -1- ((S) -2- phenylpropionyl) pyrrolidines -2- formic acid esters (140mg,
97%).LC/MS(APCI+)m/z 611-2(M+H)+。
Example 11E
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- benzene
Base -1- [(2R*) -2- phenylpropionyl] pyrrolidines -2- formic acid
Mixture of the example 11D (80mg, 0.164mmol) in methanol (1.5mL) and the aqueous LiOH of 6M (0.5mL) is existed
It is stirred 3 hours at 50 DEG C.By adding the 4M HCl in dioxanes, pH is adjusted to 1.Mixture is concentrated to dryness.Add
Add methylene chloride (2mL), and mixture is filtered by syringe type filter.Rough material is purified via chromatography, is used in
Ethyl acetate/methanol (10: 1) elution in heptane 0-60%, to obtain inactive tartaric acid (2R, 3R, 4R, 5R) -3- (tert-butyl) -
4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -5- phenyl -1- ((R) -2- phenylpropionyl) pyrrolidines -2- formic acid,
By its via chiral SFC be separated into two kinds of enantiomters [instrument: Aurora-1, column:IC, 5%-30% first
Alcohol: CO2, 10 minutes@3mL/ minutes, 150 bars.First compound of elution is (2R, 3R, 4R, 5R) -3- (tert-butyl) -4-
((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -5- phenyl -1- ((S) -2- phenylpropionyl) pyrrolidines -2- formic acid
(26mg, 40.6%)；Room temperature, retention time=4.701 minute.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.62 (b,
3H), 7.34 (db, J=28.4Hz, 3H), 7.23 (t, J=7.3Hz, 2H), 7.20-6.98 (m, 5H), 5.00 (s, 1H), 4.46
(s, 1H), 3.63 (s, 3H), 3.49-3.25 (m, 4H), 2.44-2.39 (m, 1H), 2.23 (s, 1H), 1.05 (s, 3H), 0.77
(s, 9H)；MS(ESI+)m/z 583.2(M+H)+.The second compound of elution is title compound (27mg, 42.2%)；Room
Temperature, retention time=5.519 minute.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.61 (s, 3H), 7.37 (s, 3H),
7.23 (t, J=7.3Hz, 2H), 7.08 (t, J=22.6Hz, 5H), 4.99 (s, 1H), 4.46 (s, 1H), 3.62 (s, 3H),
3.46-3.25 (m, 4H), 2.44-2.39 (m, 1H), 2.22 (s, 1H), 1.03 (s, 3H), 0.74 (s, 9H)；MS(ESI+)m/z
583.2(M+H)+。
Example 12
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
By (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2-
Formic acid esters (example 7B, 20mg, 0.05mmol, 1.0 equivalent) is dissolved in sodium acetate/acetate buffer (pH=4) in methanol.It will
2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (0.4M in methyl alcohol, 187 μ L, 0.075mmol, 1.5 equivalents) is added in bottle.
Add NaBH3CN (0.22M in acetate buffer, 300 μ L, 0.065mmol, 1.2 equivalents), and reaction is stirred at room temperature
When mixing 14.Reactant is dried under nitrogen flowing, without further purification i.e. in next step.Residue is dissolved in 3: 2 tetrahydro furans
It mutters/methanol (500 μ L).Addition is in H2LiOH monohydrate (20mg, 0.5mmol, 10 equivalent) in O (100 μ L), and will reaction
It is stirred at 45 DEG C 3 hours (shown and completed by LC/MS).Solvent is removed under nitrogen flowing.By residue with 800 μ L 1M
Aqueous HCl acidification, and with 500 μ L CH3CN dilution.Reaction mixture is loaded directly into injection ring and uses preparative
LC method trifluoroacetic acid 8 is purified, to provide title compound (22.5mg, 67% yield).1HNMR (400MHz, 120 DEG C,
Dimethyl sulfoxide-d6∶D2O=9: 1 (v/v)) δ ppm 8.31 (s, 1H), 7.54 (s, 3H), 7.40-7.19 (m, 3H), 5.22 (d,
J=7.0Hz, 1H), 4.49 (d, J=2.4Hz, 1H), 3.79 (s, 3H), 3.64-3.46 (m, 2H), 3.33 (d, J=14.9Hz,
1H), 2.38-2.09 (m, 2H), 1.55 (d, J=63.9Hz, 4H), 1.13 (d, J=60.8Hz, 5H), 0.96 (s, 9H),
0.89-0.49 (m, 1H)；MS(APCI+)m/z 561.9(M+H)+。
Example 13
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 13A
(2S, 3R, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -
1,2- dicarboxylic acid esters
By (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
(core 22,0.349g, 0.996mmol) is dissolved in methylene chloride (3mL), and adds triethylamine (0.450mL, 3.23mmol), so
The 1M isopropyl chlorocarbonate (2.00mL, 2.000mmol) in toluene is added dropwise afterwards.Reaction is stirred 4 hours at ambient temperature,
Then concentration and using 24g silicagel column with the gradient of 5-80% ethyl acetate/heptane carry out purifying 30 minutes, with provide (2S,
3R, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -5- (2- methoxyphenyl) -4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters
(350mg, 0.802mmol, 81% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.68-7.59 (m, 1H),
7.19 (ddd, J=8.8,7.5,1.7Hz, 1H), 6.91 (dd, J=8.3,1.0Hz, 1H), 6.84 (td, J=7.5,1.0Hz,
1H), 5.54 (d, J=8.3Hz, 1H), 5.45 (dd, J=8.4,2.6Hz, 1H), 4.64 (s, 1H), 4.48 (d, J=3.2Hz,
1H), 4.19 (q, J=7.1Hz, 2H), 3.77 (s, 3H), 3.28 (s, 6H), 2.90 (t, J=2.9Hz, 1H), 1.23 (t, J=
7.1Hz, 3H), 0.96 (s, 9H)；MS(ESI+)m/z 437(M+H)+。
Example 13B
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -3- (tert-butyl) -5- (2- methoxyphenyl) pyrrolidines -
1,2- dicarboxylic acid esters
Example 13A (0.35g, 0.802mmol) and tetrahydrofuran (20mL) are added in 50mL pressure bottleIn 2800 aqueous slurry of nickel (0.9g, 6.90mmol).Mixture is stirred 6 hours at 50psi hydrogen and 50 DEG C, and
Stirred at ambient temperature 10 hours.Reaction is filtered and removes solvent in a vacuum, to provide (2S, 3S, 4S, 5S) -2- second
Base 1- isopropyl 4- amino -3- (tert-butyl) -5- (2- methoxyphenyl) pyrrolidines -1,2- dicarboxylic acid esters (0.340g,
0.84mmol)。1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.67 (dd, J=7.6,1.8Hz, 1H), 7.18 (td, J=
7.8,1.7Hz, 1H), 6.94 (dd, J=8.2,1.0Hz, 1H), 6.89 (td, J=7.4,1.1Hz, 1H), 5.18 (d, J=
6.9Hz, 1H), 4.63 (p, J=6.2Hz, 1H), 4.29 (d, J=3.3Hz, 1H), 4.19-4.11 (m, 2H), 3.80 (s, 3H),
3.65 (dd, J=6.9,2.7Hz, 1H), 2.01 (t, J=3.1Hz, 1H), 1.23 (t, J=7.0Hz, 3H), 1.04 (d, J=
6.2Hz, 3H), 0.98 (s, 9H), 0.91 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 407(M+H)+。
Example 13C
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (isopropyl oxygen
Base carbonyl) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid
To 5- (tert-butyl)-Benzaldehyde,2-methoxy (37.5mg, 0.195mmol), example 13B (66mg, 0.162mmol)
It is with zinc chloride (II) (22.13mg, 0.162mmol) molten in sodium acetate/acetate buffer (pH=4,1mL) in methanol
When adding sodium cyanoborohydride (15.30mg, 0.244mmol) in liquid, and reaction being stirred 54 at ambient temperature.Solvent is existed
It is removed under nitrogen.Residue methylene chloride and water are diluted.Water phase is extracted with methylene chloride (3x1mL).Solvent is removed,
And by gained residue be dissolved in 2mL methanol and with lithium hydroxide (19.44mg, 0.812mmol) 0.5mL water in.It will mixing
Object stirs 4 hours at 45 DEG C.Solvent is removed, rough material is acidified with the aqueous HCl of 2N (450 μ L), is absorbed in methylene chloride
In, and using have 12g silicagel column 3: 1: 4 ethyl acetate/ethyl alcohol/heptane solvent system purify, with obtain (2S, 3S, 4S,
5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (isopropoxy carbonyl) -5- (2- methoxyl group
Phenyl) pyrrolidines -2- formic acid hydrochloric acid (71mg, 0.120mmol, 74.0% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δ
Ppm 7.56 (dd, J=7.7,1.7Hz, 1H), 7.20 (ddd, J=8.2,7.3,1.8Hz, 1H), 7.14 (dd, J=8.5,
2.6Hz, 1H), 6.97 (d, J=2.6Hz, 1H), 6.94-6.85 (m, 2H), 6.72 (d, J=8.5Hz, 1H), 5.24 (d, J=
6.3Hz, 1H), 4.63 (p, J=6.2Hz, 1H), 4.36 (d, J=1.8Hz, 1H), 3.62 (s, 3H), 3.59 (d, J=
13.7Hz, 1H), 3.45 (s, 3H), 3.31 (d, J=13.7Hz, 1H), 2.32 (dt, J=1.7,0.8Hz, 1H), 1.20 (s,
9H), 1.04 (d, J=6.2Hz, 3H), 0.98 (s, 9H), 0.90 (d, J=6.3Hz, 3H)；MS(ESI+)m/z 555(M+H)+。
Example 14
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (difluoro-methoxy) phenyl] -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid
Example 14A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- (difluoro-methoxy) phenyl) -4-
Nitro-pyrrole alkane -2- formic acid esters
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoro into the methylene chloride (10mL) in ice bath
Methoxyl group) phenyl) -4- nitro-pyrrole alkane -2- formic acid esters (core 15,1.0g, 2.59mmol) and one drop n,N-Dimethylformamide
Middle dropwise addition cyclohexanecarbonyl chloride (0.415mL, 3.11mmol).It stirs the mixture for 2 hours.When temperature is warmed to environment temperature
When, methylene chloride (20mL) w is added, and mixture is washed with brine, through MgSO4It is dried, filtered and concentrated.Residue is existed
It is purified on 12g silicagel column via chromatography, the ethyl acetate in heptane is titled to provide with the gradient elution of 0-40%
Close object, 1.28g (100% yield).LC/MS(ESI+)m/z 497.24(M+H)+。
Example 14B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- (difluoro-methoxy)
Phenyl) pyrrolidines -2- formic acid esters
Will in pressure bottle (50mL) example 14A (300mg, 0.604mmol), tetrahydrofuran (20mL) and-
The mixture of 2800 aqueous slurry of nickel (2.5g, 19.17mmol) vibrates 20 hours at ambient temperature, filters and is concentrated.It will be thick residual
Excess is dissolved in methylene chloride (20mL), is washed with brine, through MgSO4It is dried, filtered and concentrated to provide title compound
It is used in next step by (300mg, 100%) without further purification.LC/MS(APCI+)m/z 467(M+H)+。
Example 14C
(2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- (difluoro-methoxy) phenyl) -4-
(((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidines -2- formic acid
By 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (29.0mg, 0.141mmol), example 14B (60mg, 0.129mmol)
It is with zinc chloride (II) (3.51mg, 0.026mmol) mixed in sodium acetate/acetate buffer (pH=4,2mL) in methanol
Object is closed to stir at ambient temperature 10 minutes.It adds sodium cyanoborohydride (12.1mg, 0.193mmol), mixture is stirred for 3
Hour, and solvent is removed under stress.Residue is dissolved in ethyl acetate (10mL), is washed with brine, through MgSO4It is dry
It is dry, it filters and is concentrated.(ethyl acetate/methanol (10: 1) in heptane is washed with 0-40% for the purifying carried out via chromatography
It is de-) provide intermediate ester (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- (difluoromethoxy
Base) phenyl) -4- (((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidines -2- formic acid esters.By the ester
It is dissolved in methanol (1.5mL) and the aqueous LiOH of 6M (0.5mL).Mixture is stirred 3 hours at 50 DEG C, and by addition two
4M HCl in oxane is adjusted to pH 1-2.Solvent is removed, and by residue using ammonium acetate method via HPLC into
Row purifying, to provide title compound (64mg, 79.2% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm 8.25
(s, 1H), 8.09 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=48.9Hz, 3H), 5.37 (s, 1H), 3.84 (s, 3H), 3.59-
(3.15 m, 5H), 2.64 (s, 1H), 2.35 (s, 1H), 1.76-1.06 (m, 10H), 0.94 (s, 9H)；MS(ESI+)m/z
628.2(M+H)+。
Example 15
(2S, 3S, 4S, 5S) -1- (benzenesulfonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid example 15A
(2S, 3R, 4S, 5S) -4- nitro -1- benzenesulfonyl -3- tert-butyl -5- phenyl-pyrrolidin -2- Ethyl formate
By triethylamine (CAS# 121-44-8,112 μ L, 0.81mmol, 1.3 equivalents) and benzene sulfonyl chloride (CAS# 98-09-
9,95 μ L, 0.74mmol, 1.2 equivalents) core 7 (200mg, 0.62mmol, 1.0 equivalent) is added at anhydrous methylene chloride (3mL)
In agitating solution in.Reaction mixture is stirred at room temperature overnight, and is stirred 4 hours at 45 DEG C.Reaction mixture is used
Water washing, and organic layer is separated and is concentrated in a vacuum.Crude mixture is passed through into flashchromatography on silica gel (heptane/acetic acid second
Ester 100/0 to 80/20) purifying, to provide title compound (230mg, 80%).LC/MS(ESI+)m/z 461.4(M+H)+。
Example 15B
(2S, 3S, 4S, 5S) -4- amino -1- benzenesulfonyl -3- tert-butyl -5- phenyl-pyrrolidin -2- Ethyl formate
At room temperature, zinc powder (490mg, 7.50mmol, 15.0 equivalent) is added to (2S, 3R, 4S, 5S) -4- nitro -1-
Benzenesulfonyl -3- tert-butyl -5- phenyl-pyrrolidin -2- formic acid (230mg, 0.50mmol, 1.0 equivalent) is at ethyl acetate (3mL)
In the solution in acetic acid (1mL).Reaction is heated to 60 DEG C and continues 1 hour.Reaction is filtered over celite, with acetic acid second
Ester and methylene chloride washing, are concentrated to dryness, and in NaHCO3It is distributed between saturated aqueous solution and methylene chloride.Organic layer is concentrated
To provide title compound (208mg, 96%), it is used in next step without further purification.LC/MS(ESI+)m/
z 431.6(M+H)+。
Example 15C
(2S, 3S, 4S, 5S) -1- benzenesulfonyl -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- benzene
Base-pyrrolidines -2- Ethyl formate
By NaBH3CN (20mg, 0.31mmol, 1.3 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -1- benzene sulfonyl
Base -3- tert-butyl -5- phenyl-pyrrolidin -2- Ethyl formate (104mg, 0.24mmol, 1.0 equivalent) and 5- tert-butyl -2- methoxy
Base-benzaldehyde (CAS# 85943-26-6,52mg, 0.28mmol, 1.2 equivalent) is acetic acid/sodium acetate buffer in methanol
In solution in (96mg acetic acid, 61mg sodium acetate, 2mL methanol).Reaction mixture is stirred at room temperature 1 hour.Solvent is existed
It is removed under vacuum.Residue is distributed between methylene chloride and water.Organic phase is concentrated to dryness, and residue is passed through into silica gel
Flash chromatography (heptane/ethyl acetate 100/0 to 90/10) purifying, to provide title compound (97mg, 66%).LC/MS
(ESI+)m/z 608.1(M+H)+。
Example 15D
(2S, 3S, 4S, 5S) -1- benzenesulfonyl -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- benzene
Base-pyrrolidines -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -1- benzenesulfonyl -3- tert-butyl -4- (5- tert-butyl -2- methoxyl group-benzyl
Base amino) the solution use of -5- phenyl-pyrrolidin -2- Ethyl formate (97mg, 0.16mmol, 1.0 equivalent) in methanol (2mL)
LiOH (1.0M in water, 480 μ L, 0.48mmol, 3 equivalents) processing, and be stirred overnight at 45 DEG C.After the reaction was completed, by solvent
It removes under vacuum, and adds water.Acquired solution is acidified to pH=6 with the aqueous HCl 1N of 1N and is extracted with dichloromethane.It will
Organic phase is concentrated to dryness, and residue is purified by flashchromatography on silica gel (methylene chloride/methanol 100/0 to 94/6), with
It provides title compound (52mg, 56%).1H NMR (400MHz, CDCl3- d) δ ppm 7.54 (dd, J=8.4,1.2Hz, 2H),
7.44-7.51 (m, 1H), 7.32-7.39 (m, 2H), 7.28-7.31 (m, 1H), 7.15-7.25 (m, 3H), 6.96-7.09 (m,
3H), 6.57 (d, J=8.7Hz, 1H), 5.25-5.35 (m, 2H), 5.01 (s, 1H), 3.99 (d, J=13.8Hz, 1H), 3.28
(d, J=5.8Hz, 1H), 3.12 (s, 3H), 2.37 (s, 1H), 1.22-1.29 (m, 9H), 1.05-1.15 (m, 9H)；LC/MS
(ESI+)m/z 579.7(M+H)+。
Example 16
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid
In 4mL bottle, by (2S, 3S, 4S, 5S)-tert-butyl 4- (((the bromo- 2- methoxypyridine -3- base of 5-) methyl) ammonia
Base) -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters (example 25C, 20.0mg, 0.032mmol,
1.0 equivalents) and dichloro [4,5- bis- chloro- bis- (2, the 6- bis- -3- amyl phenyl) imidazoles -2- subunits of 1,3-] (3- chloropyridine base) palladium
(II) (PEPPSI-IPentCl, 2.7mg, 0.0032mmol, 0.1 equivalent) is dissolved in tetrahydrofuran (0.5mL), is purged with nitrogen
And it is stirred at room temperature.It adds cyclobutyl zinc bromide (0.5M, 127 μ L, 0.64mmol, 2.0 equivalents), and will react at room temperature
Stirring 30 minutes.Solvent is removed under nitrogen flowing.Residue is dissolved in pure trifluoroacetic acid (1mL) and is stirred at room temperature
2 hours.Solvent is removed under nitrogen flowing.By residue reconstruct in dimethyl sulfoxide/acetonitrile.Reactant is loaded directly into
Purified in injection ring and using preparative LC method trifluoroacetic acid 8, with provide title compound (15.6mg, 74.0%
Yield).1HNMR (400MHz, 120 DEG C, dimethyl sulfoxide-d6∶D2O=9: 1 (v/v)) δ ppm 7.83-7.78 (m, 1H),
7.60-7.46 (m, 2H), 7.40-7.26 (m, 3H), 7.20 (s, 1H), 5.23 (d, J=6.9Hz, 1H), 4.50 (d, J=
2.1Hz, 1H), 3.65 (s, 3H), 3.56 (d, J=8.3Hz, 2H), 3.44-3.32 (m, 2H), 2.42-2.19 (m, 4H),
2.07-1.76 (m, 4H), 1.72-1.40 (m, 4H), 1.32-1.01 (m, 5H), 1.01-0.91 (m, 10H)；MS(APCI+)m/z
548.1(M+H)+。
Example 17
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid
Example 17A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4-
Nitro-pyrrole alkane -2- formic acid esters
At ambient temperature, to the cyclohexanecarbonyl chloride (0.228mL, 1.707mmol) and one in methylene chloride (4mL)
It drips in n,N-Dimethylformamide and oxalyl chloride is added dropwise (4mL, 2M are in dioxanes).It stirs the mixture for 30 minutes, solvent is gone
It removes, adds fresh methylene chloride (2mL), and mixture is concentrated again.It will be added dropwise in the residue in methylene chloride (2mL)
To (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- methoxypyridine -3- base) -4- nitro-pyrrole alkane -2- formic acid esters (core
12,500mg, 1.423mmol) and triethylamine (0.297mL, 2.134mmol) it is mixed in methylene chloride (10mL) in ice bath
It closes in object, keeps temperature to be lower than 0 DEG C during addition.By reaction mixture stir 2 hours, and add methylene chloride (20mL) and
Water (10mL).Organic layer is washed with brine, through Na2SO4It is dried, filtered and concentrated.By residue on 24g silicagel column via
Chromatography purifying, the ethyl acetate in heptane is with the gradient elution of 0-40%, to obtain title compound, 650mg (99%
Yield).LC/MS(APCI+)m/z 462(M+H)+。
Example 17B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- methoxypyridine -3-
Base) pyrrolidines -2- formic acid esters
It will be added in 250mL pressure bottle in the example 17A (600mg, 1.300mmol) in tetrahydrofuran (20mL)In 2800 aqueous slurry of nickel (2.2g, 16.87mmol).It is small that mixture is vibrated to 23 at ambient temperature under 50psi hydrogen
When, it filters and is concentrated to provide title compound (560mg, 100% yield), it is used in next step without further purification
In rapid.LC/MS(APCI+)m/z 432.35(M+H)+。
Example 17C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid
By 5- (tert-butyl)-Benzaldehyde,2-methoxy (CAS#:85943-26-6) (39.2mg, 0.204mmol), (2S,
3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) pyrrolidines -2-
Formic acid esters (80mg, 0.185mmol) and zinc chloride (II) (5.05mg, 0.037mmol) are that sodium acetate/acetic acid in methanol is slow
Mixture in fliud flushing (pH=4,2mL) stirs 10 minutes at ambient temperature.Addition sodium cyanoborohydride (17.47mg,
0.278mmol).Reaction mixture is stirred 1 hour, and by solvent in N2Lower removal.By residue with ethyl acetate (10mL)
It is diluted with water (10mL).Organic layer is washed with brine, through Na2SO4It is dried, filtered and concentrated.Via color on 10g silicagel column
Spectrometry carry out purifying (ethyl acetate/methanol (10: 1) in heptane is eluted with 0-40%) provide ester (2S, 3S, 4S,
5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (cyclohexane carbo) -5- (2- methoxy
Yl pyridines -3- base) pyrrolidines -2- formic acid esters, it is dissolved in methanol (1.5mL) and the aqueous LiOH of 6M (0.5mL).By mixture
It is stirred 3 hours at 50 DEG C.Solvent is removed, is added water (1mL), and pH is adjusted to about 4 by addition 2M aqueous HCl.It will
Sediment filtering is washed with water and dries in an oven to provide title compound, 75mg (69.8% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.05 (d, J=4.6Hz, 1H), 7.95 (s, 1H), 7.15 (dd, J=8.6,
2.6Hz, 1H), 6.98 (d, J=2.5Hz, 1H), 6.91 (t, J=6.2Hz, 1H), 6.75 (d, J=8.5Hz, 1H), 5.27 (s,
1H), 448 (s, 1H), 3.81 (s, 3H), 3.58 (d, J=13.3Hz, 1H), 3.51 (s, 3H), 3.49 (s, 1H), 3.33 (d, J
=13.6Hz, 2H), 3.2 (s, 1H), 2.38 (s, 1H), 1.71-1.26 (m, 7H), 1.21 (s, 9H), 1.17-1.02 (m, 3H),
0.97 (s, 9H)；MS(ESI+)m/z 580.2(M+H)+。
Example 18
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 18A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro -1-
((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
With
Example 18B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro -1-
((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
To (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro-pyrrole
The dichloro of alkane -2- formic acid esters (core 11,740mg, 2.031mmol) and triethylamine (0.849mL, 6.09mmol) cooling in ice bath
In mixture in methane (20mL) be added dropwise tetrahydro -2H- pyrans -2- formic acid (CAS# 51673-83-7) (396mg,
3.05mmol).It stirs the mixture for 1 hour, while temperature is warmed to environment temperature.It adds methylene chloride (20mL), and will
Mixture is washed with brine, through MgSO4It is dried, filtered and concentrated.Residue is purified on 40g silicagel column via chromatography,
Ethyl acetate elution in heptane.First compound of elution is example 18A (2S, 3R, 4S, 5S)-ethyl 3- (tertiary fourth
Base) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- first
Acid esters, 360mg (37.2% yield).LC/MS(APCI+)m/z 477.35(M+H)+.The second compound of elution is example 18B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro -1- ((S)-tetrahydro -2H-
Pyrans -2- carbonyl) pyrrolidines -2- formic acid esters, 340mg (35.1% yield).LC/MS(APCI+)m/z 477.35(M+H)+。
Example 18C
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -1-
((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
It will be added in 50mL pressure bottle in the example 18B (360mg, 0.755mmol) in tetrahydrofuran (20mL)In 2800 aqueous slurry of nickel (998mg, 7.65mmol).It is small that mixture is vibrated to 16 at ambient temperature under 50psi hydrogen
When, it filters and is concentrated to provide title compound (330mg, 98% yield), it is used in next step without further purification
In rapid.LC/MS(APCI+)m/z 447(M+H)+。
Example 18D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
By 5- (tert-butyl)-Benzaldehyde,2-methoxy (25.8mg, 0.134mmol), example 18C (60mg, 0.134mmol)
It is with zinc chloride (II) (3.66mg, 0.027mmol) mixed in sodium acetate/acetate buffer (pH=4,2mL) in methanol
It closes object to stir at ambient temperature 10 minutes, to provide colourless solution.Addition sodium cyanoborohydride (12.66mg,
0.202mmol), it and stirs the mixture for 30 minutes.By solvent in N2Lower removal, and by residue on 4g silicagel column via color
Spectrometry purifying, ethyl acetate/methanol (10: 1) in heptane with the gradient elution of 0-40%, with provide ester (2S, 3S, 4S,
5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2- (dimethylamino) pyridine -3-
Base) -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters, it is dissolved in methanol (1.5mL) and 6M is aqueous
In LiOH (0.5mL).Mixture is stirred 3 hours at 50 DEG C, is adjusted to pH by adding the 4M HCl in dioxanes
4-5, and mixture is concentrated to dryness.Residue is added in methylene chloride (2mL), is filtered, and purified via chromatography, is used
Methanol in methylene chloride is with the gradient elution of 0-20%, to provide title compound (52mg, 65.1% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.23-8.13 (m, 2H), 7.17-7.10 (m, 1H), 6.98 (d, J=2.6Hz,
1H), 6.95 (dd, J=7.5,4.8Hz, 1H), 6.72 (d, J=8.5Hz, 1H), 5.61 (s, 1H), 5.55 (s, 1H), 460 (s,
1H), 3.76 (d, J=11.5Hz, 1H), 3.63 (d, J=13.6Hz, 1H), 3.54 (d, J=6.7Hz, 1H), 3.47 (s, 3H),
3.27 (d, J=13.7Hz, 1H), 3.20 (s, 1H), 2.65 (d, J=0.9Hz, 6H), 2.61 (s, 1H), 2.39-2.34 (m,
1H), 1.66 (s, 2H), 1.42 (d, J=37.5Hz, 4H), 1.19 (s, 9H), 1.00 (s, 9H)；MS(ESI+)m/z 595.3(M
+H)+。
Example 19
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 19A
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -1-
((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Replace example 10B with example 18A, title compound is prepared according to program described in example 10C.LC/MS(APCI
+)m/z 447.3(M+H)+。
Example 19B
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2- (diformazan
Base amino) pyridin-3-yl) -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid
Replace example 18C with example 19A, title compound is prepared according to program described in example 18D.1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.17 (d, J=5.4Hz, 1H), 7.91 (s, 1H), 7.13 (ddd, J=8.3,
5.6,2.6Hz, 1H), 6.98 (d, J=2.8Hz, 1H), 6.94 (d, J=4.7Hz, 1H), 6.72 (d, J=8.5Hz, 1H),
5.61 (d, J=0.9Hz, 1H), 5.40 (d, J=6.5Hz, 1H), 4.84 (s, 1H), 4.6 (d, J=3.2Hz, 1H), 3.65
(s, 1H), 3.53 (s, 1H), 3.49 (s, 1H), 3.46 (d, J=9.0Hz, 3H), 3.30 (d, J=12.0Hz, 1H), 3.25 (s,
1H), 2.63 (d, J=16.5Hz, 6H), 2.36 (s, 1H), 1.79 (s, 2H), 1.45 (d, J=10.8Hz, 4H), 1.19 (d, J
=3.8Hz, 9H), 1.00 (d, J=3.5Hz, 9H)；MS(ESI+)m/z 595.3(M+H)+。
Example 20
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(is disliked
Alkane -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid
By 2- (tetrahydro -2H- pyrans -2- base) acetic acid (0.4M in methylene chloride, 139 μ L, 0.056mmol, 1.3 equivalents)
It is added in 4mL bottle.Add pure Ghosez reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, 17 μ L,
0.13mmol, 3.0 equivalents), and reaction is stirred at room temperature 10 minutes.Addition is in 1: 1 tetrahydrofuran/pyridine (500 μ L)
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- phenylpyrrole
Alkane -2- formic acid esters (example 34D, 20mg, 0.043mmol, 1.0 equivalent), and reaction mixture is stirred at room temperature 1 hour.
Solvent is removed under nitrogen flowing, and residue is dissolved in 3: 2 tetrahydrofurans/methanol (0.5mL).Addition is in H2O(100μ
L the LiOH monohydrate (16mg, 0.4mmol, 7.1 equivalent) in), and reaction is stirred overnight at 45 DEG C.By solvent in nitrogen
It is removed under air-flow.The residue aqueous HCl of 800 μ L 1M is acidified, and with 400 μ L CH3CN dilution.Use preparative reverse phase
HPLC MS method trifluoroacetic acid 8 is purified (15.7mg, 54% yield).1HNMR (400MHz, 120 DEG C, dimethyl sulfoxide-d6
∶D2O=9: 1 (v/v)) δ ppm 7.61-7.30 (m, 5H), 7.24 (dd, J=8.6,2.5Hz, 1H), 7.06-6.99 (m, 1H),
6.81 (d, J=8.7Hz, 1H), 534 (dd, J=22.5,7.1Hz, 1H), 4.72-4.55 (m, 1H), 3.89-3.67 (m, 3H),
3.60-3.53 (m, 4H), 3.53-3.41 (m, 1H), 3.30-3.19 (m, 1H), 2.36-2.12 (m, 2H), 1.79-1.27 (m,
6H), 1.21 (s, 9H), 0.99 (s, 10H)；MS(APCI+)m/z 565.1(M+H)+。
Example 21
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 21A
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- (((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl)
Methyl) amino) -5- phenyl -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid
By 2- chloro- 5- (trifluoromethyl) cigarette aldehyde (132mg, 0.629mmol), example 10C (230mg, 0.571mmol) and chlorine
Change zinc (II) and is that the mixture in sodium acetate/acetate buffer (pH=4,2mL) in methanol stirs 10 at ambient temperature
Minute, to provide colourless solution.It adds sodium cyanoborohydride (23.53mg, 0.374mmol), and stirs the mixture for 30 minutes.
By solvent in N2Lower removal dilutes residue ethyl acetate (20mL) and water (10mL).Organic layer is washed with brine, is passed through
MgSO4It dries, filters, and is concentrated.Residue is purified on 12g silicagel column via chromatography, the acetic acid in heptane
Ethyl ester/methanol (10: 1) is with the gradient elution of 0-40%, to provide ester racemic-(2R, 3R, 4R, 5R)-ethyl 3- (tertiary fourth
Base) -4- (((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) -5- phenyl -1- ((R)-tetrahydro -2H- pyrrole
Mutter -2- carbonyl) pyrrolidines -2- formic acid esters, it is dissolved in methanol (1.5mL) and the aqueous LiOH of 4M (0.5mL).Mixture is existed
It is stirred 3 hours at 50 DEG C, and pH to 4-5 is adjusted by 4M HCl of the addition in dioxanes, and purify via chromatography, be used in
Methanol in methylene chloride uses the gradient elution of 0-20%, to provide title compound (136mg, 42% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.30 (s, 1H), 7.59 (d, J=7.5Hz, 2H), 7.51 (d, J=2.4Hz,
1H), 7.31 (t, J=7.3Hz, 2H), 7.25 (d, J=7.1Hz, 1H), 5.38 (s, 1H), 4.51 (s, 1H), 3.81 (s, 3H),
3.48-3.41 (m, 2H), 3.30 (s, 1H), 2.28 (s, 1H), 1.74-1.27 (m, 6H), 0.97 (s, 9H)；MS(ESI+)m/z
564.2(M+H)+。
Example 21B
(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- (((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) ammonia
Base) -5- phenyl -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid
With
Example 21C
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) ammonia
Base) -5- phenyl -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid
By the racemic compound of example 21A via SFC chirality post separation, 5%-50% methanol: CO2, 10 minutes@2mL/
Minute, 150 bars；Column:IC.First compound of elution is example 21B (25mg, 19.23% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.29 (t, J=1.5Hz, 1H), 7.60 (d, J=7.4Hz, 2H), 7.51 (d, J=
2.4Hz, 1H), 7.31 (t, J=7.3Hz, 2H), 7.25 (d, J=7.3Hz, 1H), 5.37 (s, 1H), 4.49 (s, 1H), 3.81
(d, J=1.1Hz, 3H), 3.77 (d, J=11.4Hz, 1H), 3.64-3.58 (m, 1H), 3.47 (s, 1H), 3.40 (s, 1H),
3.29 (s, 1H), 3.20 (s, 1H), 2.67-2.59 (m, 1H), 2.27 (s, 1H), 1.73-1.25 (m, 6H), 0.96 (d, J=
0.9Hz, 9H)；MS(ESI+)m/z 564.2(M+H)+.The second compound of elution is example 21C (45mg, 34.6% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.29 (dd, J=2.5,1.2Hz, 1H), 7.59 (d, J=7.4Hz, 2H),
7.51 (d, J=2.5Hz, 1H), 7.31 (t, J=7.4Hz, 2H), 7.25 (d, J=7.2Hz, 1H), 5.37 (s, 1H), 4.50
(s, 1H), 3.80 (s, 3H), 3.76 (s, 1H), 3.49-3.41 (m, 2H), 3.27 (d, J=15.2Hz, 3H), 2.67-2.59
(m, 1H), 2.27 (s, 1H), 1.73-1.28 (m, 6H), 0.97 (s, 9H)；MS(ESI+)m/z 564.2(M+H)+。
Example 22
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 22A
(2S, 3S, 4R, 5S)-tert-butyl 1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- nitro -5- benzene
Base pyrrolidines -2- formic acid esters
At 25 DEG C, by core 37 (1.2g, 3.29mmol) and triethylamine (0.918mL, 6.59mmol) in methylene chloride
Solution in (14.97mL) is handled dropwise with cyclohexanecarbonyl chloride (0.551mL, 4.12mmol), is stirred 2 hours, full with washing
With aqueous NaHCO3(5mL) and 1N NH4The washing of OH (1mL) aqueous solution, is concentrated to provide residue.By rough material 10mL heptane
Grinding.At ambient temperature after 0.5 hour, collect sediment (1.5g).Rough material is dissolved in 3mL methylene chloride and is loaded into
On 12g column, with gradient elution 20 minutes of 0-70% ethyl acetate/heptane, with provide desired product (2S, 3R, 4S,
5S)-tert-butyl 1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters
(1.405g, 2.96mmol, 90% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.55 (d, J=6.9Hz,
2H), 7.31-7.17 (m, 3H), 5.61 (d, J=3.0Hz, 2H), 4.62 (d, J=3.9Hz, 1H), 3.26 (dd, J=4.0,
2.6Hz, 1H), 3.15 (s, 3H), 2.16 (s, 1H), 1.67 (s, 2H), 1.51 (s, 10H), 1.22 (d, J=6.0Hz, 10H),
1.08 (t, J=10.0Hz, 2H), 0.84 (d, J=7.6Hz, 1H)；MS(ESI+)m/z 475(M+H)+。
Example 22B
(2S, 3S, 4S, 5S)-tert-butyl 4- amino -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- benzene
Base pyrrolidines -2- formic acid esters
It is packed into 250mL Parr oscillator and is then washed for several times with tetrahydrofuran with waterNickel:
2800 aqueous slurries (3.6g, 61.3mmol).Example 22A (1.405g, 2.96mmol) and tetrahydrofuran are added into mixture
(45.0mL), and then mixture argon gas is used into hydrogen purge.Reaction is stirred under the hydrogen of 50psig at ambient temperature
It mixes 16 hours.It is removed in a vacuum by material filtering and by solvent, with offer (2S, 3S, 4S, 5S)-tert-butyl 4- amino -1-
(cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid esters (1.3g, 2.92mmol, 99%
Rate).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.56 (bs, 2H), 7.31 (t, J=7.5Hz, 2H), 7.22 (t, J=
7.4Hz, 1H), 5.02 (d, J=7.3Hz, 1H), 4.33 (d, J=4.7Hz, 1H), 3.65 (dd, J=7.3,4.6Hz, 1H),
3.13 (s, 3H), 2.32 (s, 1H), 2.15 (d, J=12.9Hz, 1H), 1.62 (d, J=10.2Hz, 2H), 1.46 (s, 10H),
1.30-1.10 (m, 2H), 1.21 (s, 3H), 1.19 (s, 3H), 1.05 (m, 2H), 0.82 (bs, 2H)；MS(ESI+)m/z 445
(M+H)+。
Example 22C
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
To 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (33.2mg, 0.162mmol), example 22B (60mg, 0.135mmol)
It is with zinc chloride (II) (18.39mg, 0.135mmol) molten in sodium acetate/acetate buffer (pH=4,1mL) in methanol
Sodium cyanoborohydride (12.72mg, 0.202mmol) is added in liquid, and reaction is stirred 2 hours at ambient temperature.By solvent
It removes under a nitrogen.By residue methylene chloride and H2O dilution, and water phase is extracted with methylene chloride (3x1mL).By solvent
Removal, and gained residue is subjected to chromatography using 12g silicagel column, divided with the gradient elution 20 of 0-80% ethyl acetate/heptane
Clock is dissolved in trifluoroacetic acid (0.5mL) and stirs 2 hours at ambient temperature to provide residue (90mg).By trifluoro
Acetic acid removal, and rough material is purified using trifluoroacetic acid method by reverse phase, with acquisition (2S, 3S, 4S, 5S) -1- (ring
Hexane carbonyl) -4- (((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) -3- (2- methoxy propane -2-
Base) -5- Phenylpyrrolidine -2- methanoic acid trifluoro acetic acid (66mg, 0.095mmol, 70.7% yield).1HNMR (400MHz, diformazan
Base sulfoxide-d6) δ ppm 8.33 (s, 1H), 7.58 (m, 3H), 7.31 (t, J=7.4Hz, 2H), 7.24 (t, J=7.3Hz, 1H),
5.24 (d, J=7.2Hz, 1H), 4.52 (d, J=3.5Hz, 1H), 3.81 (s, 3H), 3.58 (d, J=14.9Hz, 2H), 3.42
(d, J=14.9Hz, 1H), 3.14 (s, 3H), 2.65 (s, 1H), 2.23 (s, 1H), 1.64 (d, J=9.8Hz, 2H), 1.49 (s,
2H), 1.24 (m, 1H), 1.19 (s, 3H), 1.18 (s, 3H), 1.16 (m, 1H), 1.07 (bs, 3H), 0.77 (bs, 1H)；MS
(ESI+)m/z 578(M+H)+。
Example 23
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2S*, 3S*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 23A
(2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -1- ((2R*, 3R*) -3- isopropyl-tetrahydro-furan -2- carbonyl
Base) -5- phenyl-pyrrolidin -2- Ethyl formate
With
Example 23B
(2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -1- ((2S*, 3S*) -3- isopropyl-tetrahydro-furan -2- carbonyl
Base) -5- phenyl-pyrrolidin -2- Ethyl formate is at 0 DEG C, outside racemic cis 3- (propane -2- base) butyl oxide link -2- formic acid
(CAS# 1808432-51-0,122mg, 0.77mmol, 1.3 equivalent) adds in the stirred suspension in methylene chloride (5mL)
Ghosez ' s reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, 237 μ L, 1.77mmol, 3.0 equivalents).By reaction mixture
Stirred 5 minutes at 0 DEG C, and add core 7 (190mg, 0.59mmol, 1.0 equivalent) and diisopropylethylamine (411 μ L,
2.36mmol, 4.0 equivalents) solution in methylene chloride.Reaction mixture is stirred 10 minutes at 0 DEG C and is stirred at room temperature
It mixes 1.5 hours.Reaction mixture is washed with water, and organic phase is concentrated to dryness.Residue is purified into (heptan on silica gel
Alkane/ethyl acetate 100/0 to 85/15), to provide title compound (mixture of diastereoisomer, 190mg, 70%).
Example 23C
(2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1- ((2R*, 3R*) -3- isopropyl-tetrahydro-furan -2- carbonyl
Base) -5- phenyl-pyrrolidin -2- Ethyl formate
With
Example 23D
(2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1- ((2S*, 3S*) -3- isopropyl-tetrahydro-furan -2- carbonyl
Base) -5- phenyl-pyrrolidin -2- Ethyl formate
At room temperature, zinc powder (490mg, 7.50mmol, 15.0 equivalent) is added to (2S, 3R, 4S, 5S) -4- nitro -3-
Tert-butyl -1- ((2R, 3R) -3- isopropyl-tetrahydro-furan -2- carbonyl) -5- phenyl-pyrrolidin -2- Ethyl formate and (2S,
3R, 4S, 5S) -4- nitro -3- tert-butyl -1- ((2S, 3S) -3- isopropyl-tetrahydro-furan -2- carbonyl) -5- phenyl-pyrrol
Alkane -2- Ethyl formate (230mg, 0.50mmol, 1.0 equivalent) is in the solution in ethyl acetate (3mL) and acetic acid (1mL).It will
Reaction is heated to 60 DEG C and continues 2 hours.Reaction is filtered over celite, is washed and is concentrated to dryness with ethyl acetate.It will slightly produce
Object is in saturation NaHCO3It is distributed between aqueous solution and methylene chloride.Organic phase is concentrated.Residue is purified on silica gel
(methylene chloride/methanol 100/0 to 99/1), with provide title compound (mixture of diastereoisomer, 170mg,
96%).LC/MS(ESI+)m/z 431.6(M+H)+。
Example 23E
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((2R*, 3R*) -3-
Isopropyl-tetrahydro-furan -2- carbonyl) -5- phenyl-pyrrolidin -2- Ethyl formate
With
Example 23F
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((2S*, 3S*) -3-
Isopropyl-tetrahydro-furan -2- carbonyl) -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (23mg, 0.36mmol, 1.3 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -
1- ((2R, 3R) -3- isopropyl-tetrahydro-furan -2- carbonyl) -5- phenyl-pyrrolidin -2- Ethyl formate and (2S, 3S, 4S,
5S) -4- amino -3- tert-butyl -1- ((2S, 3S) -3- isopropyl-tetrahydro-furan -2- carbonyl) -5- phenyl-pyrrolidin -2- first
Acetoacetic ester (85mg, 0.20mmol, 1.0 equivalent) and 5- tert-butyl -2- Methoxy-benzaldehyde (CAS#85943-26-6,
45mg, 0.24mmol, 1.2 equivalent) it is acetic acid/sodium acetate buffer (96mg acetic acid, 61mg sodium acetate, 2mL first in methanol
Alcohol) in solution in.Reaction is stirred at room temperature 1 hour.Solvent is removed under vacuum.By residue in methylene chloride and water
Between distribute.Organic phase is concentrated to dryness, and residue is purified into (methylene chloride/methanol 100/0 by flashchromatography on silica gel
To 98/2), to provide title compound (mixture of diastereoisomer, 96mg, 79%).LC/MS(ESI+)m/z 607.7
(M+H)+。
Example 23G
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(2S*, 3S*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
At room temperature, the solution by example 23E and example 23F (96mg, 0.15mmol, 1.0 equivalent) in methanol (2mL)
It is handled with LiOH 1.0M (450 μ L, 0.45mmol, 3.0 equivalent) in water, and is stirred overnight at 45 DEG C.By solvent true
The lower removal of sky, adds water, and acquired solution is extracted with ethyl acetate.Organic phase is concentrated to dryness.On silica gel by residue
(methylene chloride/methanol 100/0 to 97/3) is purified, (34mg, 39%, the second of elution is non-right to provide title compound
Reflect isomers).Spatial chemistry is any distribution.1H NMR (400MHz, DMSO-d6, 100 DEG C) δ ppm 7.67 (br.s.,
2H), 7.26-7.47 (m, 3H), 7.18 (d, J=7.3Hz, 1H), 7.00 (br.s., 1H), 6.78 (d, J=8.6Hz, 1H),
5.39 (br.s., 1H), 4.57 (br.s., 1H), 4.14 (br.s., 1H), 3.68-3.84 (m, 2H), 3.56 (br.s., 3H),
3.49-3.61 (m, 2H), 3.40 (d, J=13.2Hz, 1H), 2.37 (br.s., 1H), 1.78-2.11 (m, 3H), 1.48
(br.s., 1H), 1.25 (s, 9H), 1.05 (s, 9H), 0.83 (br.s., 3H), 0.47 (br.s., 3H).LC/MS(ESI+)m/z
579.90(M+H)+.Note: example I-104 (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl)
Methyl] amino } -5- phenyl -1- [(2R*, 3R*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid is also from chromatography
In separate, the first diastereoisomer (30mg, 34%) as elution.LC/MS(ESI+)m/z 579.90(M+H)+。
Example 24
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- fluorophenyl) pyrrolidines -2- formic acid
Example 24A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- nitro-pyrrole
Alkane -2- formic acid esters
At 0 DEG C, to (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- fluorophenyl) -4- nitro-pyrrole alkane -2- first
The solution of acid esters (core 23,10.5g, 31.06mmol) and triethylamine (10.0mL, 71.44mmol) in methylene chloride (100mL)
Middle addition cyclohexanecarbonyl chloride (5.4mL, 40.38mmol).Mixture is stirred 30 minutes at 0 DEG C, is then stirred at 25 DEG C
It mixes 1 hour.LC/MS shows to be fully converted to desired product.Mixture is diluted with methylene chloride (20mL), uses saturated water
Property sodium bicarbonate (50mL) and salt water (100mL) washing, through MgSO4It is dried, filtered and concentrated.Residue is passed through into silica
Column chromatography (elutes) purifying with 50% petrol ether/ethyl acetate, to provide title compound (2S, 3R, 4S, 5S)-ethyl 3-
(tert-butyl) -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters (8.33g, 18.6mmol,
59.9% yield).LC-MS(ESI+)m/z 449(M+H)+。
Example 24B
Ethyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- fluorophenyl) pyrroles
Alkane -2- formic acid esters
Under an inert atmosphere, to (2S, 3R, 4S, 5S)-ethyl -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- fluorobenzene
Base) -4- nitro-pyrrole alkane -2- formic acid esters (example 24A, 6.0g, 13.39mmol) in acetic acid (69.5mL, 1208.7mmol) and
Zinc (13.0g, 201.45mmol) is added in solution in ethyl acetate (394.5mL, 4029mmol).By gained mixture 55
It stirs 1 hour and then cools to room temperature at DEG C, diluted with ethyl acetate (150mL) and filter to remove solid.Filtrate is concentrated
It is extremely dry.Residue is distributed between ethyl acetate (150mL) and saturated sodium bicarbonate aqueous solution (100mL).Organic layer is used
Salt water (100mL) washing, through MgSO4It is dried, filtered and concentrated.Residue is purified by prep-HPLC (ammonium carbonate method),
To provide title compound (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2- fluorobenzene
Base) pyrrolidines -2- formic acid esters (3.67g, 8.77mmol, 65.5% yield).1HNMR (400MHz, CDCl3) δ ppm 8.11 (t, J
=7.6Hz, 1H), 7.22-7.32 (m, 2H), 6.99-7.12 (m, 1H), 5.38 (d, J=6.8Hz, 1H), 4.56 (d, J=
3.6Hz, 1H), 4.22-4.31 (m, 2H), 3.75-3.77 (m, 1H), 1.96-2.07 (m, 2H), 1.62-1.83 (m, 3H),
1.20-1.51 (m, 12H), 0.89 (s, 9H), 0.55-0.75 (m, 2H)；LC-MS(ESI+)m/z 419(M+H)+。
Example 24C
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (ring
Hexane carbonyl) -5- (2- fluorophenyl) pyrrolidines -2- formic acid esters
By example 24B (A-1671634.0, CP, 60.9mg, 0.146mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy
(40.7mg, 0.212mmol) is dissolved in methanol (1mL), and is stirred 1 hour at ambient temperature.Add sodium cyanoborohydride
(34.0mg, 0.541mmol), and reaction is stirred for 16 hours at ambient temperature.Reaction is dilute with dimethyl sulfoxide (1mL)
It releases, filter and is purified using ammonium acetate method by reverse phase, to provide title compound (47.4mg, 45%).1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.85 (s, 1H), 7.29 (s, 1H), 7.19-7.03 (m, 3H), 6.92
(d, J=2.6Hz, 1H), 6.73 (d, J=8.5Hz, 1H), 5.40 (s, 1H), 4.54 (d, J=2.4Hz, 1H), 4.12 (ddq, J
=10.7,7.4,3.8Hz, 2H), 3.53 (s, 3H), 3.48 (d, J=14.1Hz, 2H), 3.32 (d, J=13.7Hz, 1H),
2.43-2.11 (m, 2H), 1.67 (s, 2H), 1.53 (s, 2H), 1.19 (d, J=3.4Hz, 18H), 0.97 (s, 9H)；MS(ESI
+)m/z 595(M+H)+。
Example 24D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- fluorophenyl) pyrrolidines -2- formic acid
Example 24C (44.4mg, 0.075mmol) is dissolved in methanol (1mL).It adds LiOH (1M, 0.5mL, 0.5mmol)
And reaction is heated to 50 DEG C and is kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, dimethyl sulfoxide is used
(1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide the title compound for being in trifluoroacetate
Object (39.6mg, 78%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.75 (s, 1H), 7.33 (q, J=
7.0Hz, 1H), 7.22-7.10 (m, 3H), 7.02 (d, J=2.5Hz, 1H), 6.79 (d, J=8.5Hz, 1H), 5.44 (d, J=
6.9Hz, 1H), 4.53 (d, J=1.9Hz, 1H), 3.70 (d, J=13.7Hz, 1H), 3.66 (d, J=7.0Hz, 1H), 3.58
(s, 3H), 3.45 (d, J=13.7Hz, 1H), 2.50 (s, 1H), 2.31 (s, 1H), 1.72-1.49 (m, 4H), 1.34-1.04
(m, 15H), 0.98 (s, 9H)；MS(ESI+)m/z 567(M+H)+。
Example 25
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyl group -5- phenylpyridine -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid
Example 25A
(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- Phenylpyrrolidine -2-
Formic acid esters
Replace core 2 with core 6, title compound is prepared according to program described in example 7A.1HNMR (400MHz, dimethyl
Sulfoxide-d6, 120 DEG C) and δ ppm 7.61-7.55 (m, 2H), 7.30-7.21 (m, 3H), 5.66-5.55 (m, 2H), 4.58 (d, J=
3.6Hz, 1H), 2.96 (t, J=3.2Hz, 1H), 2.24-2.12 (m, 1H), 1.84-1.61 (m, 4H), 1.51 (s, 9H),
1.44-1.04 (m, 6H), 1.00 (s, 9H)；MS(ESI+)m/z 459(M+H)+。
Example 25B
(2S, 3S, 4S, 5S)-tert-butyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2-
Formic acid esters
Replace example 7A with example 25A, title compound is prepared according to program described in example 7B.1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.56 (d, J=7.3Hz, 2H), 7.32 (t, J=7.5Hz, 2H), 7.23
(t, J=7.3Hz, 1H), 5.02 (d, J=7.1Hz, 1H), 4.29 (d, J=4.0Hz, 1H), 3.63 (dd, J=7.2,3.6Hz,
1H), 2.17 (d, J=0.8Hz, 1H), 2.01 (d, J=4.1Hz, 1H), 1.62 (d, J=8.2Hz, 2H), 1.46 (d, J=
0.8Hz, 11H), 1.33-1.01 (m, 6H), 0.98 (d, J=0.7Hz, 9H)；MS(ESI+)m/z 429(M+H)+。
Example 25C
(2S, 3S, 4S, 5S)-tert-butyl 4- (((the bromo- 2- methoxypyridine -3- base of 5-) methyl) amino) -3- (tertiary fourth
Base) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters
By the bromo- 2- methoxyl group cigarette aldehyde (0.529g, 2.450mmol) of 5- and (2S, 3S, 4S, 5S)-tert-butyl 4- amino -3-
(tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters (example 25B, 1g, 2.333mmol) is mixed in methanol
In (12mL), and when reaction is stirred at room temperature 14.Then disposably addition sodium cyanoborohydride (0.740g,
11.78mmol), and by reaction continue to be stirred at room temperature 1.5 days.After this, solvent is removed in a vacuum, and by residue
It is absorbed in 100mL water and 100mL CH2Cl2In, and be transferred on separatory funnel.Separatory funnel is shaken, these are mutually separated, and
Water layer is used into CH again2Cl2It is extracted twice (each 100mL).By combined organic matter through Na2SO4It dries, filters and in vacuum
Middle concentration.Silica gel chromatography (being eluted with 5% to 30% ethyl acetate-heptane) provides impure title compound 1.02g.It should
Material is used in next step without other purifying.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.00 (m, 1H),
7.59 (m, 2H), 7.40-7.19 (m, 4H), 5.17 (d, J=6.9Hz, 1H), 4.40 (d, J=2.7Hz, 1H), 3.68 (s,
3H), 3.41-3.21 (m, 3H), 2.26 (m, 1H), 2.19 (m, 1H), 1.68-1.02 (m, 10H), 1.43 (s, 9H), 0.98 (s,
9H)；MS(ESI+)m/z 628.0(M+H)+。
Example 25D
(2S, 3S, 4S, 5S)-tert-butyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- (((2- methoxyl group -5- phenyl pyrazoline
Pyridine -3- base) methyl) amino) -5- Phenylpyrrolidine -2- formic acid esters
By from example 25C impure compound (0.257g, 0.409mmol), phenylboric acid (0.065g,
0.531mmol) and Pd (PPh3)4(tetrakis triphenylphosphine palladium (0), 0.047g, 0.041mmol) uses dioxanes (5mL) and potassium carbonate
The solution processing of (0.113g, 0.818mmol) in water (1.25mL), and reaction mixture is heated overnight at 100 DEG C.This it
Afterwards, mixture is diluted with ethyl acetate, and with water and salt water washing.By organic layer through Na2SO4It dries, filters, and true
Aerial concentration.Silica gel chromatography (being eluted with 5% to 40% ethyl acetate-heptane) provides title compound, and (0.074g, 29% obtains
Rate).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.21 (m, 1H), 7.59-7.21 (m, 9H), 5.20 (m, 1H), 4.42
(m, 1H), 3.74 (s, 3H), 3.51-3.32 (m, 3H), 2.29 (m, 1H), 2.16 (m, 1H), 1.67-0.97 (m, 9H), 1.40
(s, 9H), 0.99 (s, 9H), 0.84 (m, 1H)；MS(ESI+)m/z 626.1(M+H)+。
Example 25E
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyl group -5- phenylpyridine -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid
Will the example 25D (0.074g, 0.118mmol) in methylene chloride (1.7mL) with trifluoroacetic acid (0.82mL,
It 10.64mmol) handles, and reaction is stirred at room temperature overnight.Then mixture is concentrated in a vacuum, and rough material is led to
Reversed-phase HPLC is crossed to existC8(2)5umIt is purified on AXIA column (30mm × 75mm).Use second
The gradient of nitrile (A) and 0.1% trifluoroacetic acid (B) in water, flow velocity are that (0-1.0 minutes 5%A, 1.0-8.5 divided in 50mL/ minutes
Clock linear gradient 5%-100%A, 8.5-11.5 minute 100%A, 11.5-12.0 minutes linear gradient 95%-5%A), to mention
For title compound (0.0345g, 51% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.27 (d, J=
2.5Hz, 1H), 7.82-7.21 (m, 11H), 5.29 (d, J=7.0Hz, 1H), 4.52 (d, J=2.3Hz, 1H), 3.77 (s,
3H), 3.62 (m, 3H), 3.43 (d, J=14.3Hz, 1H), 2.45 (m, 1H), 2.26 (m, 1H), 1.70-1.03 (m, 9H),
1.00 (s, 9H), 0.77 (m, 1H)；MS(ESI+)m/z 570.2(M+H)+。
Example 26
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid
Example 26A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- nitro-pyrrole
Alkane -2- formic acid esters
At 0 DEG C, by (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (4- fluorophenyl) -4- nitro-pyrrole alkane -2- first
The solution of acid esters (core 33,1.90g, 5.62mmol) and triethylamine (1.565mL, 11.23mmol) in methylene chloride (30mL)
It is handled with cyclohexanecarbonyl chloride (0.906g, 6.18mmol).Mixture is stirred 30 minutes at 0 DEG C, is then stirred at room temperature
When mixing 14.LC/MS shows to be fully converted to desired product.Mixture is diluted with methylene chloride (100mL), it is full with washing
With aqueous NaHCO3The washing of (30mL) and salt water (30mL), it is dried over magnesium sulfate, it filters and is concentrated.Residue is passed through into silicagel column
Chromatography (the 0-60% ethyl acetate in heptane) purifying, to provide title compound (2S, 3R, 4S, 5S)-ethyl 3-
(tert-butyl) -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- nitro-pyrrole alkane -2- formic acid esters (2g, 4.46mmol, 79%
Rate, ee=98.8%).1HNMR (400MHz, CDCl3).δ ppm 7.36-7.68 (m, 2H), 6.98-7.08 (m, 2H), δ ppm
5.41-5.53 (m, 1H), 5.20-5.34 (m, 1H), 4.76 (d, J=8Hz, 1H), 4.32 (q, J=8Hz, 2H), 3.09-3.12
(m, 1H), 2.31-2.36 (m, 1H), 1.38-2.06 (m, 7H), 1.37 (t, J=8Hz, 3H), 1.08-1.33 (m, 3H), 1.03
(s, 9H)；LC/MS(ESI+)m/z 449.2(M+H)+。
Example 26B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (4- fluorophenyl) pyrroles
Alkane -2- formic acid esters
Zinc is added in the solution in ethyl acetate (10mL) and acetic acid (10mL) to example 26A (2.0g, 4.46mmol)
(5.83g, 89mmol).Mixture is stirred 1 hour at 60 DEG C.Most of solvent is evaporated.By residue methylene chloride
(100mL) dilution, is washed with saturated sodium bicarbonate aqueous solution (30mL) and salt water (30mL), through Na2SO4It dries, filters and is subtracting
Pressure concentration.Residue petroleum ether (5x2mL) is ground to provide title compound (2S, 3S, 4S, 5S)-ethyl 4- amino-
3- (tert-butyl) -1- (cyclohexane carbo) -5- (4- fluorophenyl) pyrrolidines -2- formic acid esters (1.49g, 3.56mmol, 80%
Rate).1HNMR (400MHz, CDCl3) δ ppm 7.35-7.64 (m, 2H), 6.97-7.12 (m, 2H), 5.00 (d, J=4Hz, 1H),
4.51 (d, J=4Hz, 1H), 4.24 (q, J=8Hz, 2H), 3.58-3.64 (m, 1H), 1.99-2.05 (m, 2H), 1.31-1.70
(m, 8H), 1.30 (t, J=8Hz, 3H), 1.23-1.27 (m, 1H), 1.04-1.14 (m, 2H), 1.03 (s, 9H), 0.55-0.65
(m, 1H)；LC/MS(ESI+)m/z 419.3(M+H)+。
Example 26C
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid
By 2- chloro- 5- (trifluoromethyl) cigarette aldehyde (33.0mg, 0.158mmol), example 26B (60mg, 0.143mmol) and chlorine
Change zinc (II) and is that the mixture in sodium acetate/acetate buffer (pH=4,2mL) in methanol stirs 10 at ambient temperature
Minute.It adds sodium cyanoborohydride (23.53mg, 0.374mmol), and stirs the mixture for 1 hour until as by LC/MS institute
The completion of monitoring.Solvent is removed, and residue is dissolved in methylene chloride (10mL), is washed with brine, through MgSO4It is dry,
It filters and is concentrated.(ethyl acetate/methanol (10: 1) in heptane is with the gradient of 0-40% for the purifying carried out via chromatography
Elution) intermediate (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- is provided
(((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidines -2- formic acid esters, is dissolved in methanol
In (1.5mL) and the aqueous LiOH of 4M (0.5mL).Mixture is stirred 3 hours and by addition in dioxanes at 50 DEG C
PH is adjusted to 4-5 by 4M HCl.Gained mixture is purified with trifluoroacetic acid method via HTP, is in trifluoro second to provide
Title compound (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- (((2- of hydrochlorate
Methoxyl group -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidines -2- formic acid.(44mg, 44.3% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.32 (s, 1H), 7.62 (s, 2H), 7.56 (d, J=2.4Hz, 1H), 7.08 (t, J
=8.7Hz, 2H), 5.23 (d, J=7.0Hz, 1H), 4.47 (d, J=2.5Hz, 1H), 3.83 (s, 3H), 3.58-3.47 (m, 4H),
2.34 (s, 1H), 2.22 (s, 1H), 1.70-1.04 (m, 10H), 0.97 (s, 9H)；MS(ESI+)m/z 580.2(M+H)+。
Example 27
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid
Example 27A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- (tert-butyl) -2- methoxypyridine -3- base) methyl)
Amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters
By (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2-
Formic acid esters (example 7B, 1.393g) and 5- (tert-butyl) -2- methoxyl group cigarette aldehyde (0.068g, 0.352mmol) are at methanol (3.5mL)
In be stirred at room temperature 1 hour.Then disposably addition sodium cyanoborohydride (0.111g, 1.759mmol), and will react in room
It is stirred overnight under temperature.Then reaction mixture is concentrated in a vacuum, remaining residue is then absorbed in CH2Cl2And water
In.These are mutually separated, and water layer is used into CH again2Cl2It is extracted twice.By combined organic extract through Na2SO4It dries, filters
And be concentrated in vacuo, and gained thick residue is purified by silica gel chromatography, the elution of 0 to 20% ethyl acetate-heptane of use, with
It provides title compound 0.127g (63% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.93 (d, J=
2.7Hz, 1H), 7.59 (m, 2H), 7.33-7.22 (m, 4H), 5.20 (d, J=6.9Hz, 1H), 4.51 (d, J=2.8Hz, 1H),
4.10 (m, 2H), 3.66 (s, 3H), 3.44 (m, 2H), 3.30 (m, 1H), 2.32 (m, 1H), 2.19 (m, 1H), 1.65-1.06
(m, 9H), 1.22 (s, 9H), 1.18 (t, J=7.0Hz, 3H), 0.98 (s, 9H), 0.83 (m, 1H)；MS(ESI+)m/z 578.3
(M+H)+。
Example 27B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid
By example 27A (0.127g, 0.220mmol) and 1M lithium hydroxide aqueous solution (1.8mL, 1.800mmol) in tetrahydro
It is stirred together at 45 DEG C in furans (1.8mL) and methanol (1.800mL).After 3 hours, mixture is concentrated in a vacuum, is led to
It crosses and removes excessive water with acetonitrile azeotropic.Obtained solid 0.25mL trifluoroacetic acid is handled, is absorbed in ethyl acetate simultaneously
It is applied on silicagel column, is eluted with 4: 3: 1 heptane-ethyl acetates-ethyl alcohol is (isocratic), to provide thick title compound (trifluoro second
Hydrochlorate), then it is further dried at 80 DEG C under vacuum, to provide title compound (0.164g, 96% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.96 (m, 1H), 7.54 (m, 2H), 7.34-7.23 (m, 4H), 5.20 (d, J
=6.8Hz, 1H), 4.48 (d, J=2.5Hz, 1H), 3.65 (s, 3H), 3.54-3.45 (m, 3H), 3.34 (m, 1H), 2.36-
2.26 (m, 2H), 1.66-1.04 (m, 9H), 1.23 (s, 9H), 0.98 (s, 9H), 0.83 (m, 1H)；MS(ESI+)m/z 550.3
(M+H)+。
Example 28
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 28A
(2S, 3R, 4S, 5S) -3- tert-butyl -1- (2,3- Dihydro-benzofuran -2- carbonyl) -4- nitro -5- phenyl-pyrrole
Cough up alkane -2- Ethyl formate
At 0 DEG C, to racemic 2,3- dihydro -2- benzofurancarboxylic acid (CAS# 1914-60-9,200mg,
1.22mmol, 2.1 equivalents) Ghosez ' s reagent (1- chloro- N, N, 2- tri- are added in the agitating solution in methylene chloride (3mL)
Methyl-1-propylene amine, 250 μ L, 1.86mmol, 1.9 equivalents).Reaction mixture is stirred 5 minutes at 0 DEG C, and adds core 7
(190mg, 0.59mmol, 1.0 equivalent) and diisopropylethylamine (430 μ L, 2.46mmol, 4.2 equivalent) are in methylene chloride
Solution.Reaction mixture is stirred at room temperature 1 hour.Reaction mixture is quenched with aqueous ammonium chloride solution, it is dilute with ethyl acetate
It releases, and by organic layer water and salt water washing.Combined organic layer is dried over magnesium sulfate, it is filtered and concentrated to dry.It will be remaining
Object is purified (heptane/ethyl acetate 95/5 to 70/30) on silica gel, with provide title compound (diastereoisomer
Mixture, 170mg, 62%).LC/MS(ESI+)m/z 467.6(M+H)+。
Example 28B
(2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1- (2,3- Dihydro-benzofuran -2- carbonyl) -5- phenyl-pyrrole
Cough up alkane -2- Ethyl formate
At room temperature, zinc powder (475mg, 7.30mmol, 20.0 equivalent) is added to (2S, 3R, 4S, 5S) -3- tert-butyl -
1- (2,3- Dihydro-benzofuran -2- carbonyl) -4- nitro -5- phenyl-pyrrolidin -2- Ethyl formate (170mg, 0.37mmol,
1.0 equivalents) in the solution in ethyl acetate (7mL) and acetic acid (2mL).Reaction is heated to 100 DEG C and continues 2 hours.It will be anti-
It should filter, be washed with ethyl acetate and methylene chloride over celite, and be concentrated to dryness.By crude product in saturation NaHCO3It is water-soluble
It is distributed between liquid and ethyl acetate.By organic layer water and salt water washing.Combined organic layer is dried over magnesium sulfate, and filtering is simultaneously
It is concentrated to dryness.The title compound (170mg, 100%) for obtaining the mixture in diastereoisomer, by it without further pure
Change i.e. in next step.LC/MS(ESI+)m/z 437.6(M+H)+。
Example 28C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- (2,3- dihydros-benzene
And furans -2- carbonyl) -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (15mg, 0.24mmol, 1.3 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -
1- (2,3- Dihydro-benzofuran -2- carbonyl) -5- phenyl-pyrrolidin -2- Ethyl formate (81mg, 0.18mmol, 1.0 equivalent)
It is in methanol with 5- tert-butyl -2- Methoxy-benzaldehyde (CAS# 85943-26-6,42mg, 0.22mmol, 1.2 equivalent)
In solution in acetic acid/sodium acetate buffer (96mg acetic acid, 61mg sodium acetate, 2mL methanol).Reaction is stirred at room temperature 1.5
Hour.Solvent is removed under vacuum.Residue is distributed between methylene chloride and water.Organic phase is concentrated to dryness, and will
Residue purifies (heptane/ethyl acetate 95/5 to 70/30) by flashchromatography on silica gel, (non-right to provide title compound
The mixture for reflecting isomers, through 2 steps, 72mg, 63%).LC/MS(ESI+)m/z 613.9(M+H)+。
Example 28D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((S*) -2,3- bis-
Hydrogen-benzofuran -2- carbonyl) -5- phenyl-pyrrolidin -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1-
(2,3- Dihydro-benzofuran -2- carbonyl) -5- phenyl-pyrrolidin -2- Ethyl formate (72mg, 0.12mmol, 1.0 equivalent) exists
The LiOH1.0M (240 μ L, 0.24mmol, 2.0 equivalent) of solution in water in methanol (1mL), and be stirred overnight at 40 DEG C.
Reaction mixture methylene chloride is diluted and uses acetic acid.It is then dry through magnesium sulfate by organic layer water and salt water washing
It is dry, it filters and is concentrated in a vacuum.Residue is purified by silica gel chromatography (methylene chloride/methanol 100/0 to 90/10),
To provide title compound (11mg, 16%, second elution) and diastereoisomer (3mg, 4%, first elute).
LC/MS(ESI+)m/2585.80(M+H)+。
Example 29
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid
Example 29A
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- ylmethyl)-amino] -1-
Cyclohexane carbo -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (16mg, 0.26mmol, 1.3 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -
1- cyclohexane carbo -5- phenyl-pyrrolidin -2- Ethyl formate (example 7B, 86mg, 0.20mmol, 1.0 equivalent) and the tertiary fourth of 6-
Base -2- methoxv-pyridine -3- formaldehyde (47mg, 0.24mmol, 1.2 equivalent) is acetic acid/sodium acetate buffer in methanol
In solution in (96mg acetic acid, 61mg sodium acetate, 2mL methanol).Reaction is stirred at room temperature 1 hour.Under vacuum by solvent
Removal.Residue is distributed between methylene chloride and water.Organic phase is concentrated to dryness, and by residue purified (methylene chloride/
Methanol 100/0 to 98/2), to provide title compound (104mg, 90%).LC/MS(ESI+)m/z 579.0(M+H)+。
Example 29B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- ylmethyl)-amino] -1-
Cyclohexane carbo -5- phenyl-pyrrolidin -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- base-first
Base)-amino] -1- cyclohexane carbo -5- phenyl-pyrrolidin -2- Ethyl formate (104mg, 0.18mmol, 1.0 equivalent) is in methanol
Solution in (2mL) is handled with aqueous LiOH 1.0M (540 μ L, 0.54mmol, 3.0 equivalent), and mixture is stirred at 45 DEG C
Overnight.After the reaction was completed, solvent is removed under vacuum, adds water, and acquired solution is extracted with ethyl acetate.By organic phase
It is concentrated to dryness.Residue is purified on silica gel (methylene chloride/methanol 100/0 to 97/3), to provide title compound
(63mg, 64%).1H NMR (400MHz, CDCl3) δ ppm 7.31-7.44 (m, 4H), 7.17 (br.s., 2H), 6.82 (d, J=
7.5Hz, 1H), 5.20-5.34 (m, 1H), 4.68 (s, 1H), 3.86 (d, J=13.7Hz, 1H), 3.49 (d, J=13.7Hz,
1H), 3.44 (s, 3H), 3.39 (d, J=6.1Hz, 1H), 2.89-3.07 (m, 1H), 2.40 (s, 1H), 2.06 (s, 1H), 1.84
(d, J=11.8Hz, 1H), 1.69-1.80 (m, 4H), 1.35-1.52 (m, 4H), 1.29-1.34 (m, 9H), 1.08 (s, 9H)；
LC/MS(ESI+)m/z 550.9(M+H)+。
Example 30
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S) -
3,3- difluorocyclohex alkane -1- carbonyls] -5- Phenylpyrrolidine -2- formic acid
Example 30A
(2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -1- (the fluoro- cyclohexane carbo of (S) -3,3- bis-) -5- phenyl-pyrrol
Alkane -2- Ethyl formate
At 0 DEG C, by Ghosez ' s reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, CAS# 26189-59-3,
0.55mL, 4.2mmol, 1.2 equivalent) 3.3- difluorocyclohex alkane -1- formic acid (629mg, 3.8mmol, 1.1 equivalent) is added in nothing
In solution in water methylene chloride (10mL).Reaction mixture is stirred 30 minutes at 0 DEG C.Addition core 7 (1.11g,
3.5mmol, 1.0 equivalents) and diisopropylethylamine (1.82mL, 10.4mmol, 3.0 equivalent), and reaction mixture is warmed to
Room temperature simultaneously stirs 2 hours.Reaction mixture is quenched with water, and water phase is extracted with dichloromethane.Combined organic phase is existed
It is dried, filtered and concentrated on sodium sulphate.Residue is purified to (heptane/ethyl acetate 100/0 to 70/30) on silica gel,
To provide the title compound (525mg, 32%) for being in the second diastereoisomer eluted.LC/MS(ESI+)m/z 467.4(M
+H)+。
Example 30B
(2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1- (the fluoro- cyclohexane carbo of (S) -3,3- bis-) -5- phenyl-pyrrol
Alkane -2- Ethyl formate
Zinc powder (197mg, 3.0mmol, 15.0 equivalent) is added to (2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -1-
(the fluoro- cyclohexane carbo of (S) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate (95mg, 0.2mmol, 1.0 equivalent) is in second
In solution in acetoacetic ester/acetic acid (10mL/1.0mL).Reaction mixture is stirred 2 hours at 60 DEG C.Add a spatula
Zinc, and reaction mixture is stirred at room temperature overnight.Reaction mixture is filtered and is concentrated in a vacuum.By residue in silicon
(10g, dichloromethane/ethyl acetate 100/0 to 50/50) is purified on glue, (57mg, 64% obtains to provide title compound
Rate).LC/MS(ESI+)m/z 437.9(M+H)+。
Example 30C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((S) -3,3- bis-
Fluoro- cyclohexane carbo) -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (5mg, 0.12mmol, 1.3 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1-
(the fluoro- cyclohexane carbo of (S) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate (28mg, 64mmol, 1.0 equivalent) and uncle 5-
Butyl -2- methoxyl group-phenyl formaldehyde (15mg, 77mmol, 1.2 equivalent) is in acetic acid/sodium acetate/methanol buffer (2mL)
In solution.Reaction mixture is stirred at room temperature 45 minutes.Reaction mixture is concentrated, and by residue in methylene chloride and
Aqueous NaHCO3Between distribute.Organic phase is concentrated, and residue is purified into (dichloromethane/ethyl acetate on silica gel
100/0 to 95/5), to provide title compound (32mg, 82% yield).LC/MS(ESI+)m/z 613.9(M+H)+。
Example 30D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((S) -3,3- bis-
Fluoro- cyclohexane carbo) -5- phenyl-pyrrolidin -2- formic acid
LiOH (11mg, 0.27mmol, 5.0 equivalent) is added to (2S, 3S, 4S, 5S) -3- tert-butyl -4- (tertiary fourth of 5-
Base -2- Methoxy-benzylamino) -1- (the fluoro- cyclohexane carbo of (S) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate
(32mg, 0.052mmol, 1.0 equivalent) is in the solution in tetrahydrofuran/methanol/water (1.5/1.5/1).By reaction mixture
It is stirred overnight at 45-50 DEG C.Reaction mixture is acidified with aqueous HCl 1M (1 equivalent/LiOH).Mixture is concentrated and uses two
Chloromethanes extraction.Organic phase is concentrated.Residue is purified on silica gel (methylene chloride/methanol 100/0 to 95/5),
To provide title compound (29mg, 95% yield).1H NMR (400MHz, DMSO-d6, 100 DEG C) δ ppm 7.48-7.74 (m,
2H), 7.25-7.43 (m, 3H), 7.10-7.23 (m, 1H), 6.92-7.07 (m, 1H), 6.69-6.83 (m, 1H), 5.15-5.34
(m, 1H), 4.47 (br.s, 1H), 3.27-3.77 (m, 6H), 2.96 (br.s, 1H are under water peaks), 2.27-2.46 (m, 1H),
1.47-2.12 (m, 8H), 1.23 (s, 9H), 1.01 (s, 9H).LC/MS(ESI+)m/z 585.7(M+H)+。
Example 31
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -
3,3- difluorocyclohex alkane -1- carbonyls] -5- Phenylpyrrolidine -2- formic acid
Example 31A
(2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -1- (the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrol
Alkane -2- Ethyl formate
Prepare title compound as described in example 30A, as elution the first diastereoisomer (550mg,
34%).LC/MS(ESI+)m/z 467.4(M+H)+。
Example 31B
(2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1- (the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrol
Alkane -2- Ethyl formate
Zinc powder (11.6g, 177mmol, 15.0 equivalent) is added to (2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -1-
(the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate (5.50g, 11.8mmol, 1.0 equivalent) exists
In solution in ethyl acetate/acetic acid (50mL/12.8mL).Reaction mixture is stirred 45 minutes at 60 DEG C and is then filtered.
It concentrates the filtrate to dry.Residue is dissolved in methylene chloride, and uses NaHCO3Saturated aqueous solution neutralizes.By water phase dichloromethane
Alkane extraction.By combined organic phase in Na2SO4On be dried, filtered and concentrated to provide title compound (5.03g, 98%), will
It is without further purification i.e. in next step.LC/MS(ESI+)m/z 437.5(M+H)+。
Example 31C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((R) -3,3- bis-
Fluoro- cyclohexane carbo) -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (372mg, 5.92mmol, 1.2 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -
1- (the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate (2.16g, 4.94mmol, 1.0 equivalent)
It is in methanol with 5- tert-butyl -2- Methoxy-benzaldehyde (CAS# 85943-26-6,1.04g, 5.43mmol, 1.1 equivalent)
Acetic acid/sodium acetate buffer (96mg acetic acid, 61mg sodium acetate, 2mL methanol) in solution in.Reaction is stirred at room temperature 1
Hour.Solvent is removed under vacuum.Residue is distributed between methylene chloride and water.Organic phase is concentrated to dryness, and will
Residue is purified by silica gel chromatography (heptane/ethyl acetate 100/0 to 70/30), with provide title compound (2.60g,
85%).LC/MS(ESI+)m/z 613.9(M+H)+。
Example 31D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((R) -3,3- bis-
Fluoro- cyclohexane carbo) -5- phenyl-pyrrolidin -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1-
(the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate (2.60g, 4.31mmol, 1.0 equivalent) exists
LiOH1.0M (12.93mL, 12.93mmol, the 3.0 equivalent) processing of solution in water in methanol (40mL), and at 45 DEG C
It is stirred overnight.After the reaction was completed, solvent is removed under vacuum, adds water and aqueous 2N HCl, then adds methylene chloride.It will
Organic layer is separated and is concentrated to dryness.Residue is purified on silica gel (methylene chloride/methanol 100/0 to 96/4), to mention
For title compound (1.66g, 66%).1H NMR (400MHz, chloroform-d) δ ppm 7.29-7.49 (m, 5H), 7.18
(br.s., 1H), 7.07 (d, J=2.2Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 5.24 (d, J=6.1Hz, 1H), 4.67
(s, 1H), 4.11 (d, J=13.8Hz, 1H), 3.55 (d, J=13.8Hz, 1H), 3.37-3.50 (m, 1H), 3.33 (d, J=
6.3Hz, 1H), 3.25 (s, 3H), 2.48 (s, 1H), 2.01-2.26 (m, 2H), 1.41-1.95 (m, 6H), 1.27 (s, 9H),
1.09 (s, 9H)；LC/MS(ESI+)m/z 585.8(M+H)+。
Example 32
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2- methoxyl group -3- phenylpropionyl] -5- Phenylpyrrolidine -2- formic acid
Example 32A
(2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -1- ((R) -2- methoxyl group -3- phenyl-propionyl) -5- phenyl -
Pyrrolidines -2- Ethyl formate
At 0 DEG C, by Ghosez reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, CAS# 26189-59-3,245 μ
L, 1.85mmol, 3 equivalent) (R) -2- methoxyl group -3- phenyl-propionic (223mg, 1.24mmol, 2.0 equivalent) is added to anhydrous
In solution in methylene chloride (10mL).Reaction mixture is stirred 30 minutes at 0 DEG C.Successively add core 7 (198mg,
0.62mmol, 1.0 equivalents) and diisopropylethylamine (539 μ L, 3.09mmol, 5.0 equivalent), and reaction mixture is warmed to
Room temperature simultaneously stirs 1 hour.By reaction mixture in methylene chloride and NH4It is distributed between Cl saturated aqueous solution.Organic phase is existed
Na2SO4On be dried, filtered and concentrated.Residue is purified to (heptane/ethyl acetate 95/5 to 70/30) on silica gel, with
Provide the title compound (263mg) in single enantiomter.LC/MS(ESI+)m/z 483.6(M+H)+。
Example 32B
(2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1- ((R) -2- methoxyl group -3- phenyl-propionyl) -5- phenyl -
Pyrrolidines -2- Ethyl formate
Zinc powder (534mg, 8.175mmol, 15.0 equivalent) is added to (2S, 3R, 4S, 5S) -4- nitro -3- tert-butyl -
(263mg, 0.545mmol, 1.0 work as -5- phenyl-pyrrolidin -2- Ethyl formate 1- ((R) -2- methoxyl group -3- phenyl-propionyl)
Amount) in the solution in ethyl acetate/acetic acid (20mL/2.81mL).Reaction mixture is stirred 2 hours at 60 DEG C.Addition
The zinc of one spatula, and reaction mixture is stirred for 1 hour at 60 DEG C.Reaction mixture is diluted in methylene chloride, is used in combination
Aqueous NaHCO3It neutralizes.Organic phase is concentrated under vacuum.Residue is purified to (heptane/ethyl acetate on silica gel
70/30 to 30/70), to provide title compound (214mg, 87% yield).LC/MS(ESI+)m/z 453.6(M+H)+。
Example 32C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -1- ((R) -2- methoxy
Base -3- phenyl-propionyl) -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (18mg, 0.287mmol, 1.3 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -
(110mg, 0.221mmol, 1.0 work as -5- phenyl-pyrrolidin -2- Ethyl formate 1- ((R) -2- methoxyl group -3- phenyl-propionyl)
Amount) and 5- tert-butyl -2- methoxyl group-phenyl formaldehyde (50mg, 0.265mmol, 1.2 equivalent) buffered in acetic acid/sodium acetate/methanol
In solution in liquid (2mL).Reaction mixture is stirred at room temperature 1 hour.Reaction mixture is concentrated, and by residue two
Chloromethanes and aqueous NaHCO3Between distribute.Organic phase is concentrated, and residue is purified to (heptane/acetic acid second on silica gel
Ester 99/1 to 80/20), to provide title compound (116mg, 83% yield).LC/MS(ESI+)m/z 629.8(M+H)+。
Example 32D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -
2- methoxyl group -3- phenylpropionyl] -5- Phenylpyrrolidine -2- formic acid
LiOH (77.5mg, 1.38mmol, 10.0 equivalent) is added to (2S, 3S, 4S, 5S) -3- tert-butyl -4- (uncle 5-
Butyl -2- Methoxy-benzylamino) -1- ((R) -2- methoxyl group -3- phenyl-propionyl) -5- phenyl-pyrrolidin -2- formic acid second
Ester (116mg, 0.138mmol, 1.0 equivalent) is in the solution in tetrahydrofuran/methanol/water (5/5/3).Reaction mixture is existed
50 DEG C are stirred 30 minutes, are then stirred at room temperature overnight.Reaction mixture water and ethyl acetate are quenched.By this two layers point
From.Organic phase is concentrated to dryness.Residue is purified into (methylene chloride/methanol 100/0 to 96/ by flashchromatography on silica gel
4), to provide title compound (80mg, 72%).1HNMR (400MHz, chloroform-d) δ ppm 7.17-7.36 (m, 11H), 7.07
(d, J=2.4Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 5.25-5.33 (m, 1H), 4.84-4.93 (m, 2H), 4.06 (d, J
=13.8Hz, 1H), 3.54 (d, J=13.8Hz, 1H), 3.44 (s, 3H), 3.34 (d, J=6.1Hz, 1H), 3.25 (s, 3H),
3.05 (dd, J=13.7,6.8Hz, 1H), 2.97 (dd, J=13.7,7.5Hz, 1H), 2.45 (s, 1H), 1.26 (s, 9H),
1.09 (s, 9H)；LC/MS(ESI+)m/z 601.8(M+H)+。
Example 33
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) ring
Propyl] phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid
Example 33A
4,4,5,5- tetramethyl -2- (4- (1- (trifluoromethyl) cyclopropyl) phenyl) -1,3,2- bis- dislike ring pentaborane
Under a nitrogen, to the bromo- 4- of 1- (1- (trifluoromethyl) cyclopropyl) benzene (2.2g, 8.30mmol) at dioxanes (6mL)
In solution in add 4,4,4 ', 4 ', 5,5,5 ', 5 '-prestox -2,2 '-two (1,3,2- bis- dislikes ring pentaboranes) (2.64g,
10.40mmol), potassium acetate (2.42g, 24.66mmol) and dicyclohexyl (4 '-ethyls -2 ', 6 '-diisopropyls-[1,1 '-connection
Benzene] -2- base) phosphine (220mg, 0.475mmol).Mixture is stirred 6 hours at 100 DEG C, 25 DEG C is subsequently cooled to and uses second
Acetoacetic ester (50mL) dilution.Insoluble matter is isolated by filtration, and filtrate is concentrated under reduced pressure.Mixture is passed through into preparative
TLC (petroleum ether: ethyl acetate=15: 1) is purified, to provide 4,4,5,5- tetramethyl -2- (4- (1- (trifluoromethyl) cyclopropyl)
Phenyl) -1,3,2- bis- evils ring pentaborane (1.8g, 4.61mmol, 55.6% yield).1HNMR (400MHz, CDCl3)δppm
1.04 (br.s., 2H), 1.30-1.40 (m, 14H), 7.48 (d, J=7.94Hz, 2H), 7.80 (d, J=7.94Hz, 2H).
Example 33B
4- (1- (trifluoromethyl) cyclopropyl) phenol
Ring pentaborane is disliked to 4,4,5,5- tetramethyl -2- (4- (1- (trifluoromethyl) cyclopropyl) phenyl) -1,3,2- bis-
Sodium hydrate aqueous solution (3mL, 3M) is being added dropwise in the solution in ice tetrahydrofuran (30mL) but in (1.8g, 5,77mmol),
And mixture is stirred 0.5 hour at 0 DEG C.Through 5 minutes addition hydrogen peroxide (30 weight %, 3mL, 29.4mmol).It will be anti-
25 DEG C should be warmed to and continue stirring 12 hours.Aqueous NaHSO is saturated by addition3Reaction mixture is quenched.Add water.It will
Mixture is extracted with diethyl ether (100mL), and organic layer is washed with saturated brine, dry through anhydrous magnesium sulfate, and is filtered.It will
Solvent distills under reduced pressure, to provide title compound 4- (1- (trifluoromethyl) cyclopropyl) phenol (1.16g, 100% yield).1HNMR (400MHz, CDCl3) δ ppm 0.98 (br.s., 2H), 1.27-1.35 (m, 2H), 4.84 (s, 1H), 6.80 (d, J=
8.38Hz, 2H), 7.34 (d, J=7.94Hz, 2H).
Example 33C
2- hydroxyl -5- (1- (trifluoromethyl) cyclopropyl) benzaldehyde
Add example 33B (507.3mg, 2.509mmol), magnesium chloride (367.5mg, 3.86mmol) and paraformaldehyde
(537.6mg, 17.90mmol) is suspended in acetonitrile (8mL) and triethylamine (1.4mL, 10.04mmol).Gained suspension is violent
It is stirred and heated to 80 DEG C and continues 14 hours, LC/MS shows complete conversion as desired product at this time.Add the aqueous HCl of 1M
(50mL), and reaction is extracted with methylene chloride (2x50mL).By combined organic layer through MgSO4Be dried, filtered and concentrated with
It provides title compound (541.6mg, 94%).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 10.90 (s, 1H), 10.24
(s, 1H), 7.69 (d, J=2.4Hz, 1H), 7.57 (dd, J=8.6,2.4Hz, 1H), 7.00 (d, J=8.5Hz, 1H), 1.33-
1.26 (m, 2H), 1.09-1.03 (m, 2H).
Example 33D
2- methoxyl group -5- (1- (trifluoromethyl) cyclopropyl) benzaldehyde
Example 33C (546.5mg, 2.374mmol) is dissolved in n,N-Dimethylformamide (5mL), and adds potassium carbonate
(501.3mg, 3.63mmol).Gained suspension is vigorously stirred, and disposably adds iodomethane (532.4mg, 3.75mmol).
Suspension is stirred at room temperature 20 hours.It adds the aqueous NaOH of 1M (50mL), and by reaction methyl tertiary butyl ether(MTBE)
(2x50mL) extraction.Combined extract is washed with water (50mL) and salt water (50mL), then dried over magnesium sulfate, filtering is simultaneously
Concentration is to provide title compound (505.7mg, 87%).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 10.32 (s,
1H), 7.72 (dq, J=4.5,2.5Hz, 2H), 7.24 (d, J=9.3Hz, 1H), 3.91 (s, 3H), 1.35-1.29 (m, 2H),
1.12-1.05 (m, 2H)；MS(ESI+)m/z 177(M+H)+。
Example 33E
Tert-butyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- Phenylpyrrolidine -2-
Formic acid esters
Addition tert-butyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (core 6,
2.02g, 5.80mmol) it is dissolved in methylene chloride (25mL) and triethylamine (1.2mL, 8.61mmol), then add cyclohexane-carbonyl
Chlorine (1.07g, 7.30mmol).Reaction is stirred 17 hours at ambient temperature.Reaction is diluted with methylene chloride (50mL), and
With the aqueous HCl of 1M (2x50mL) and salt water washing.Organic layer is dried over sodium sulfate, filters, is then concentrated titled to provide
It closes object (2.66g, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.61-7.55 (m, 2H), 7.30-
7.21 (m, 3H), 5.66-5.55 (m, 2H), 4.58 (d, J=3.6Hz, 1H), 2.96 (t, J=3.2Hz, 1H), 2.24-2.12
(m, 1H), 1.84-1.61 (m, 4H), 1.51 (s, 9H), 1.44-1.04 (m, 6H), 1.00 (s, 9H)；MS(ESI+)m/z 459
(M+H)+。
Example 33F
Tert-butyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2-
Formic acid esters
Example 33E (2.66g, 5.80mmol) and tetrahydrofuran (65mL) are added in 120mL Parr oscillatorIn 2800 aqueous slurry of nickel (10.8g, 31.7mmol), and mixture is vibrated 16 at 50psi H2 and environment temperature
Hour.HPLC shows that starting material has been consumed.Reaction is filtered and is concentrated to provide title compound (2.48g, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.56 (d, J=7.3Hz, 2H), 7.32 (t, J=7.5Hz, 2H),
7.23 (t, J=7.3Hz, 1H), 5.02 (d, J=7.1Hz, 1H), 4.29 (d, J=4.0Hz, 1H), 3.63 (dd, J=7.2,
3.6Hz, 1H), 2.17 (d, J=0.8Hz, 1H), 2.01 (d, J=4.1Hz, 1H), 1.62 (d, J=8.2Hz, 2H), 1.46 (d,
J=0.8Hz, 11H), 1.33-1.01 (m, 6H), 0.98 (d, J=0.7Hz, 9H)；MS(ESI+)m/z 429(M+H)+。
Example 33G
Tert-butyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -5- (1- (trifluoro
Methyl) cyclopropyl) benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters
Example 33F (52.8mg, 0.123mmol) and example 33D (40.9mg, 0.167mmol) are dissolved in methanol (1mL)
And it stirs 1 hour at ambient temperature.It adds sodium cyanoborohydride (43.3mg, 0.689mmol), and will react in environment temperature
Under be stirred for 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filters and passes through RP chromatography using ammonium acetate method
It is purified, to provide title compound (51.1mg, 63%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm
7.63-7.51 (m, 2H), 7.35-7.22 (m, 3H), 7.19 (dd, J=8.4,2.4Hz, 1H), 6.95 (d, J=2.3Hz, 1H),
6.79 (d, J=8.4Hz, 1H), 5.16 (d, J=6.9Hz, 1H), 4.40 (d, J=2.7Hz, 1H), 3.56 (s, 3H), 3.46
(d, J=14.4Hz, 2H), 3.29 (d, J=13.9Hz, 1H), 2.34-2.14 (m, 2H), 1.71-1.44 (m, 4H), 1.41 (s,
9H), 1.33-0.89 (m, 19H)；MS(ESI+)m/z 657(M+H)+。
Example 33H
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) ring
Propyl] phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid
Example 33G (49.9mg, 0.076mmol) is dissolved in methylene chloride (1mL).Addition trifluoroacetic acid (0.5mL,
6.49mmol) and by reaction stir 16 hours at ambient temperature.By reaction concentration to provide in the titled of trifluoroacetate
It closes object (54.2mg, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.59 (d, J=7.4Hz, 2H),
7.39 (t, J=7.5Hz, 2H), 7.35-7.28 (m, 2H), 7.09 (d, J=2.3Hz, 1H), 6.89 (d, J=8.5Hz, 1H),
5.35 (d, J=7.1Hz, 1H), 4.53 (d, J=2.1Hz, 1H), 3.85-3.78 (m, 1H), 3.74 (d, J=13.8Hz, 1H),
3.63 (s, 3H), 3.42 (d, J=13.8Hz, 1H), 2.51 (s, 1H), 2.25 (s, 1H), 1.71-1.59 (m, 2H), 1.56-
1.45 (m, 2H), 1.32-0.93 (m, 19H)；MS(ESI+)m/z 601(M+H)+。
Example 34
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 34A
(2S, 3R, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -1,2- dioctyl phthalate
Ester
Core 7 (5.00g.15.61mmol) is dissolved in tetrahydrofuran (32mL).Addition di-tert-butyl dicarbonate (5.10g,
23.37mmol) and by reaction stirred 16 hours at 55 DEG C.The reaction is cooled to environment temperatures.Add imidazoles
(1.08g.15.86mmol) is to quench any excessive di-tert-butyl dicarbonate.Reaction is dilute with methyl tertiary butyl ether(MTBE) (250mL)
It releases, and is then washed with salt water (50mL) with the aqueous HCl of the 1M of 2x100mL.Organic matter is dried over sodium sulfate, filter and is concentrated
To provide title compound (6.40g, 98%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.55-7.48
(m, 2H), 7.28-7.17 (m, 3H), 5.58 (dd, J=8.8,3.2Hz, 1H), 5.39 (d, J=8.8Hz, 1H), 4.47 (d, J
=3.8Hz, 1H), 4.25 (qd, J=7.1,0.9Hz, 2H), 2.96 (t, J=3.5Hz, 1H), 1.29 (t, J=7.1Hz, 3H),
1.19 (d, J=0.7Hz, 9H), 1.02 (s, 9H)；MS(ESI+)m/z 420(M+H)+。
Example 34B
(2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 4- amino -3- (tert-butyl) -5- Phenylpyrrolidine -1,2- dioctyl phthalate
Ester
Example 34A (6.40g, 15.22mmol) and tetrahydrofuran (120mL) are added in 250mL Parr oscillator
'sIn 2800 aqueous slurry of nickel (19g, 146mmol), and by mixture in 50psi H2It is small with oscillation 16 under environment temperature
When.HPLC shows that starting material has been consumed.Reaction is filtered and is concentrated to provide title compound (5.94g, 97%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.51-7.46 (m, 2H), 7.28 (t, J=7.6Hz, 2H),
7.23-7.16 (m, 1H), 4.83 (d, J=7.0Hz, 1H), 4.23 (d, J=3.8Hz, 1H), 4.17 (qd, J=7.1,4.8Hz,
2H), 3.59 (dd, J=7.0,3.4Hz, 1H), 2.01 (t, J=3.6Hz, 1H), 1.25 (t, J=7.1Hz, 3H), 1.17 (s,
9H), 1.00 (s, 9H)；MS(ESI+)m/z 391(M+H)+。
Example 34C
(2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) ammonia
Base) -5- Phenylpyrrolidine -1,2- dicarboxylic acid esters
By example 34B (4.92g, 12.60mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (2.65g,
13.78mmol) it is dissolved in dichloroethanes (50mL).It adds sodium triacetoxy borohydride (4.02g, 18.97mmol), and will reaction
When stirring 14 at ambient temperature.Reaction is diluted with methylene chloride (200mL), and sudden with saturation aqueous sodium bicarbonate (50mL)
It goes out.It stirs the mixture for about 30 minutes.Organic layer is concentrated and extracts water layer with methylene chloride (2x50mL).By having for merging
Machine layer is through Na2SO4It is dried, filtered and concentrated.Residue is dissolved in heptane (35mL), and be added dropwise HCl (3M in cyclopentyl methyl ether,
8.4mL).Obtained solid is removed via filtering, and dry to provide the title compound (7.38g, 97%) for being in HCl salt.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.59 (d, J=7.5Hz, 2H), 7.36 (t, J=7.5Hz, 2H),
7.28 (t, J=7.4Hz, 1H), 7.22 (d, J=8.7Hz, 1H), 7.04 (s, 1H), 6.81 (d, J=8.6Hz, 1H), 5.12
(d, J=6.9Hz, 1H), 4.36 (d, J=2.3Hz, 1H), 4.19 (q, J=7.0Hz, 2H), 3.86-3.77 (m, 1H), 3.68
(d, J=13.6Hz, 1H), 3.61 (s, 3H), 3.40 (d, J=13.5Hz, 1H), 2.58 (s, 1H), 1.28-1.20 (m, 12H),
1.16 (s, 9H), 1.01 (s, 9H)；MS(ESI+)m/z 567(M+H)+。
Example 34D
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- phenyl
Pyrrolidines -2- formic acid esters
Example 34C (7.38g, 12.23mmol) is dissolved in methylene chloride (40mL).Addition trifluoroacetic acid (20mL,
260mmol), when and reaction being stirred 34 at ambient temperature.It will be diluted reaction concentration and with methylene chloride (250mL).It will
Organic layer is washed with the aqueous NaOH of 1M (2x100mL) and salt water (100mL), through Na2SO4It is dried, filtered and concentrated to provide title
Compound (5.71g, 100%).1HNMR (500MHz, dimethyl sulfoxide-d6) δ ppm 7.39 (d, J=7.1Hz, 2H), 7.31
(t, J=7.6Hz, 2H), 7.26-7.21 (m, 1H), 7.09 (dd, J=8.5,2.6Hz, 1H), 6.88 (d, J=2.5Hz, 1H),
6.71 (d, J=8.5Hz, 1H), 4.17-4.04 (m, 3H), 3.58 (d, J=5.9Hz, 1H), 3.52 (s, 3H), 3.35-3.27
(m, 1H), 3.12-3.05 (m, 2H), 2.09 (d, J=5.8Hz, 1H), 1.17 (d, J=7.2Hz, 12H), 0.91 (s, 9H)；MS
(ESI+)m/z 467(M+H)+。
Example 34E
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
It will be in (S)-tetrahydrofuran -2- formic acid (9.95mg, 0.086mmol, 2.0 equivalent) in methylene chloride (500 μ L)
It is added in 4mL bottle.Add pure Ghosez reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, 17 μ L, 0.13mmol,
3.0 equivalents), and reaction is stirred at room temperature 10 minutes.Addition in 1: 1 tetrahydrofuran/pyridine (500 μ L) (2S, 3S,
4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters
(example 34D, 20mg, 0.043mmol, 1.0 equivalent), and when reaction is stirred at room temperature 14.Solvent is gone under nitrogen flowing
It removes, and residue is dissolved in 3: 2 tetrahydrofurans/methanol (0.5mL).Addition is in H2LiOH monohydrate in O (100 μ L)
(20mg, 0.5mmol, 11.6 equivalent), and reaction is stirred overnight at 45 DEG C.Solvent is removed under nitrogen flowing.It will be remaining
Object is acidified with the aqueous HCl of 800 μ L 1M, and with 400 μ L CH3CN dilution.Use preparative reversed-phase HPLC MS method trifluoroacetic acid
10 are purified (15.7mg, 54% yield).1HNMR (400MHz, 120 DEG C, dimethyl sulfoxide-d6∶D2O=9: 1 (v/v)) δ
Ppm 7.60 (d, J=7.4Hz, 2H), 741 (d, J=7.3Hz, 2H), 7.41-7.29 (m, 2H), 7.26 (dd, J=8.6,
2.5Hz, 1H), 7.03 (d, J=2.5Hz, 1H), 6.82 (d, J=8.6Hz, 1H), 5.50 (d, J=6.9Hz, 1H), 4.61 (d,
J=1.9Hz, 1H), 4.23 (s, 1H), 3.92-3.85 (m, 1H), 3.82-3.63 (m, 2H), 3.60 (s, 3H), 3.42 (d, J=
13.6Hz, 1H), 2.55 (s, 1H), 1.89 (d, J=5.5Hz, 1H), 1.78 (dq, J=13.7,7.1,6.6Hz, 1H), 1.68
(s, 2H), 1.21 (s, 9H), 0.99 (s, 9H)；MS(APCI+)m/z 537.1(M+H)+。
Example 35
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cis- -
4- hydroxyl -4- propyl cyclohexane -1- carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid
Will in methylene chloride (500 μ L) (1r, 4s) -4- hydroxyl -4- propyl cyclohexane formic acid (11.9mg,
0.064mmol, 1.5 equivalents) it is added in 4mL bottle.Add pure Ghosez reagent (1- chloro- N, N, 2- trimethyl -1- propylene
Amine, 17 μ L, 0.13mmol, 3.0 equivalents), and reaction is stirred at room temperature 10 minutes.Addition is in 1: 1 tetrahydrofuran/pyridine
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- in (500 μ L)
Phenylpyrrolidine -2- formic acid esters (example 34D, 20mg, 0.043mmol, 1.0 equivalent), and when reaction is stirred at room temperature 14.
Solvent is removed under nitrogen flowing, and residue is dissolved in 3: 2 tetrahydrofurans/methanol (0.5mL).Addition is in H2O(100μL)
In LiOH monohydrate (20mg, 0.5mmol, 11.6 equivalent), and reaction is stirred overnight at 45 DEG C.By solvent in nitrogen
Flow down removal.The residue aqueous HCl of 800 μ L 1M is acidified, and with 400 μ L CH3CN dilution.Use preparative reversed-phase HPLC
MS method trifluoroacetic acid 10 is purified (14.9mg, 48% yield).1HNMR (400MHz, 120 DEG C, dimethyl sulfoxide-d6∶D2O
=9: 1 (v/v)) δ ppm 7.58 (s, 2H), 7.47-7.24 (m, 4H), 7.06 (d, J=2.6Hz, 1H), 6.84 (d, J=
8.6Hz, 1H), 5.40 (d, J=7.2Hz, 1H), 4.56 (d, J=2.0Hz, 1H), 3.94 (d, J=7.0Hz, 1H), 3.85 (d,
J=13.6Hz, 1H), 3.60 (s, 3H), 3.50 (d, J=13.5Hz, 1H), 2.57 (s, 1H), 2.17 (s, 1H), 1.62 (td, J
=12.4,3.8Hz, 2H), 1.50 (d, J=13.8Hz, 1H), 1.39 (d, J=12.2Hz, 2H), 1.21 (s, 14H), 1.11-
0.90 (m, 11H), 0.82 (t, J=6.2Hz, 3H)；MS(APCI+)m/z 607.2(M+H)+。
Example 36
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid
Example 36A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((R*) -2,3- Dihydrobenzofuranes -2- carbonyl) -5- (2-
(dimethylamino) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters
And
Example 36B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((S*) -2,3- Dihydrobenzofuranes -2- carbonyl) -5- (2-
(dimethylamino) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters
To (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro-pyrrole
Alkane -2- formic acid esters (core 1,920mg, 2.5mmol) and triethylamine (1.391mL, 9.98mmol) are in methylene chloride (30mL)
Addition 2,3- Dihydrobenzofuranes -2- phosgene (0.501g, 2.74mmol) cooling in ice bath in mixture.By mixture
It is stirred 30 minutes in ice bath and it is made to be warmed to environment temperature.It adds methylene chloride (10mL), and mixture is washed with salt
It washs, through MgSO4It is dried, filtered and concentrated.Residue is purified on 24g silicagel column through chromatography, in heptane
Ethyl acetate is with 0-25% gradient elution, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((R) -2,3- dihydrobenzene
And furans -2- carbonyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters 435mg (342%
Rate), the first compound as elution.MS(ESI+)m/z 511.2(M+H)+.The second compound of elution is title compound
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((S) -2,3- Dihydrobenzofuranes -2- carbonyl) -5- (2- (dimethylamino)
Pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters (460mg, 36.1% yield).MS(ESI+)m/z 511.2(M+H)+。
Example 36C
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- ((S*) -2,3- Dihydrobenzofuranes -2- carbonyl) -
5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -2- formic acid esters
It will be added in 250mL pressure bottle in the example 36B (450mg, 0.881mmol) in tetrahydrofuran (20mL)In 2800 aqueous slurry of nickel (950mg, 7.93mmol).By mixture with argon cleaning 4 times, then hydrogen (50psi) is used
It rinses and is vibrated 16 hours at 50 DEG C.Mixture is filtered and concentrated to it is dry, to provide the titled of 375mg (89% yield)
Object is closed, it is used in next step without further purification.LC/MS(APCI+)481(M+H)+。
Example 36D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid
By 5- (tert-butyl)-Benzaldehyde,2-methoxy (28.8mg, 0.150mmol), example 36C (60mg, 0.125mmol)
It is with zinc chloride (II) (3.40mg, 0.025mmol) mixed in sodium acetate/acetate buffer (pH=4,2mL) in methanol
Object is closed to stir at ambient temperature 10 minutes.It adds sodium cyanoborohydride (11.77mg, 0.187mmol), stirs the mixture for 1
Hour, and solvent is removed under stress.Residue is purified on 12g silicagel column via chromatography, the second in heptane
Acetoacetic ester/methanol (10: 1) is with 0-40% gradient elution, to obtain ester (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5-
(tert-butyl) -2- methoxy-benzyl) amino) -1- ((S) -2,3- Dihydrobenzofuranes -2- carbonyl) -5- (2- (dimethylamino)
Pyridin-3-yl) pyrrolidines -2- formic acid esters.The ester is dissolved in methanol (0.5mL) and the aqueous LiOH of 4M (0.5mL).By mixture
It is stirred overnight at 50 DEG C, and pH to 4-5 is adjusted by 4M HCl of the addition in dioxanes.Mixture is concentrated, is dissolved in two
In chloromethanes (2mL) and filter.Filtrate is purified on 4g silicagel column via chromatography, with methanol in methylene chloride with 0-
20% gradient elution provides 40mg (51.0% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.20 (s, 2H),
7.18-7.12 (m, 1H), 7.09 (d, J=7.1Hz, 1H), 7.04 (d, J=7.2Hz, 1H), 7.02-6.94 (m, 2H), 678
(dd, J=7.5,1.1Hz, 1H), 6.73 (d, J=8.6Hz, 1H), 6.66 (d, J=8.0Hz, 1H), 5.65 (s, 1H), 4.61
(s, 1H), 3.63 (d, J=13.8Hz, 1H), 3.57 (d, J=6.4Hz, 1H), 3.47 (d, J=0.9Hz, 3H), 3.28 (d, J
=13.7Hz, 1H), 3.18 (d, J=19.3Hz, 3H), 2.88 (s, 2H), 2.66-2.62 (m, 6H), 2.60 (s, 1H), 1.20
(s, 9H), 1.04 (s, 9H)；MS(ESI+)m/z 629.3(M+H)+。
Example 37
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (two
Methylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] pyrroles
Alkane -2- formic acid
Example 37A
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- ((R*) -2,3- Dihydrobenzofuranes -2- carbonyl) -
5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -2- formic acid esters
Replace example 36B with example 36A, title compound is prepared according to program described in example 36C.LC/MS(APCI
+)m/z 481(M+H)+。
Example 37B
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R*) -2,3- Dihydrobenzofuranes -2- carbonyl] -5- [2- (dimethyl
Amino) -3- pyridyl group] -4- [[2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl] methylamino] pyrrolidines -2- first
Acid
By 2- methoxyl group -5- (1- (trifluoromethyl) cyclopropyl) benzaldehyde (30.5mg, 0.125mmol), (2S, 3S, 4S,
5S)-ethyl 4- amino -3- (tert-butyl) -1- ((R*) -2,3- Dihydrobenzofuranes -2- carbonyl) -5- (2- (dimethylamino)
Pyridin-3-yl) pyrrolidines -2- formic acid esters (60mg, 0.125mmol) and zinc chloride (II) (3.40mg, 0.025mmol) be first
The mixture in sodium acetate/acetate buffer (pH=4,2mL) in alcohol is stirred at room temperature 10 minutes, colourless molten to provide
Liquid.It adds pure sodium cyanoborohydride (11.77mg, 0.187mmol), and mixture is stirred at room temperature 1 hour.By solvent
In N2Lower removal.Residue is purified by chromatography, the ethyl acetate/methanol (10: 1) in heptane is washed with 0-40%
It is de-, to obtain ester.The ester is dissolved in methanol (2mL) and the aqueous LiOH of 4M (0.5mL).Mixture is stirred at 40 DEG C
Night.Solvent is removed, and adds water (1mL).PH is adjusted to 4-5.The purifying carried out by chromatography (is used in CH2Cl2In
Methanol is with 0-20% gradient elution) title compound 54mg (63.5% yield) is provided.1HNMR (400MHz, dimethyl sulfoxide-
d6) δ ppm 8.17 (d, J=4.5Hz, 1H), 8.00 (s, 1H), 7.23 (dd, J=8.4,2.4Hz, 1H), 7.14 (d, J=
7.5Hz, 1H), 7.05 (d, J=2.0Hz, 2H), 6.96 (d, J=5.8Hz, 1H), 6.81 (dd, J=7.9,3.1Hz, 2H),
6.67 (d, J=8.1Hz, 1H), 5.46 (d, J=6.4Hz, 1H), 4.91 (s, 1H), 3.61 (s, 1H), 3.51 (s, 1H), 3.50
(s, 3H), 3.35-3.25 (m, 4H), 3.20 (s, 1H), 2.60 (s, 6H), 2.55 (s, 1H), 1.30-1.24 (m, 2H), 1.05
(s, 9H), 0.95 (dd, J=5.0,3.3Hz, 2H)；MS(ESI+)m/z 681.2(M+H)+。
Example 38
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 38A
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- ylmethyl)-amino] -5-
Phenyl-pyrrolidin -1,2- dioctyl phthalate 1- tert-butyl ester 2- ethyl ester
By NaBH3CN (209mg, 3.32mmol, 1.3 equivalent) is added to example 34B, and (1.00g, 2.56mmol, 1.0 work as
Amount) and 6- tert-butyl -2- methoxv-pyridine -3- formaldehyde (593mg, 3.07mmol, 1.2 equivalent) in acetic acid/sodium acetate/methanol
In solution in buffer (1.2g acetic acid, 763mg sodium acetate, 25mL methanol).Reaction mixture is stirred at room temperature 1 hour.
Solvent is removed under vacuum.Residue is distributed between methylene chloride and water.Organic phase is concentrated to dryness, and by residue
(heptane/ethyl acetate, 100/0 to 80/20) is purified on silica gel, and to provide title compound, (785mg, 54% is obtained
Rate).LC/MS(ESI+)m/z 568.9(M+H)+。
Example 38B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- ylmethyl)-amino] -5-
Phenyl-pyrrolidin -2- Ethyl formate
Trifluoroacetic acid (2mL) is added to (2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxyl group-pyrrole
Pyridine -3- ylmethyl)-amino] -5- phenyl-pyrrolidin -1,2- dioctyl phthalate 1- tert-butyl ester 2- ethyl ester (785mg, 1.38mmol, 1.0
Equivalent) in the solution in methylene chloride (12mL).Reaction is stirred at room temperature 72 hours.Solvent is removed under vacuum.It will
Residue is in methylene chloride and saturation NaHCO3It is distributed between aqueous solution.Organic phase is concentrated to dryness, and residue is passed through into silicon
Glue purified by flash chromatography (methylene chloride/methanol 100/0 to 98/2), to provide title compound (520mg, 80%).LC/MS
(ESI+)m/z 468.8(M+H)+。
Example 38C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- ylmethyl)-amino] -5-
Phenyl -1- ((S)-ttetrahydro-pyran -2- carbonyl)-pyrrolidines -2- Ethyl formate
With
Example 38D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- ylmethyl)-amino] -5-
Phenyl -1- ((R)-ttetrahydro-pyran -2- carbonyl)-pyrrolidines -2- Ethyl formate
At 0 DEG C, to ttetrahydro-pyran -2- formic acid (23mg, 0.18mmol, 1.3 equivalent) in methylene chloride (2mL)
Ghosez ' s reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, 55 μ L, 0.42mmol, 3.0 equivalents) are added in agitating solution.
Reaction mixture is stirred 5 minutes at 0 DEG C, and adds amine core 7 (65mg, 0.14mmol, 1.0 equivalent) and diisopropylethylamine
The solution of (97 μ L, 0.56mmol, 4.0 equivalent) in methylene chloride.Reaction mixture is stirred 10 minutes at 0 DEG C and in room
Temperature lower stirring 1.5 hours.Reaction mixture is washed with water, and organic phase is concentrated to dryness.Residue is carried out on silica gel
To provide two kinds of diastereoisomer example 38C, (23mg, 28%, are eluted for purifying (heptane/ethyl acetate 100/0 to 85/15)
First) and example 38D (23mg, 28%, second of elution).LC/MS(ESI+)m/z 580.8(M+H)+。
Example 38E
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- Ji Jia
Base)-amino] -5- phenyl -1- ((S)-ttetrahydro-pyran -2- carbonyl)-pyrrolidines -2- Ethyl formate (example 38C, 23mg,
0.04mmol, 1.0 equivalents) (120 μ L, 0.12mmol, 3.0 work as with LiOH 1.0M in water for solution in methanol (1mL)
Amount) processing, and mixture is stirred overnight at 45 DEG C.After completion of the reaction, the aqueous HCl of 1N is added, and under vacuum by solvent
Removal.Residue is purified on silica gel (methylene chloride/methanol 100/0 to 95/5).Product fraction is merged, and dense
It is reduced to dry to provide title compound (14mg, 63%).1HNMR (400MHz, CDCl3- d) δ ppm 7.30-7.52 (m, 4H),
7.12-7.26 (m, 2H), 6.80 (d, J=7.3Hz, 1H), 5.30 (m, 1H), 4.62 (br.s., 1H), 4.28 (br.s., 1H),
3.99 (d, J=10.8Hz, 1H), 3.68-3.85 (m, 1H), 3.56 (t, J=10.2Hz, 1H), 3.51-3.49 (m, 1H),
3.41-3.49 (m, 3H), 3.38 (d, J=5.8Hz, 1H), 2.26-2.43 (m, 1H), 1.89 (br.s., 1H), 1.42-1.78
(m, 5H), 1.24-1.37 (m, 9H), 1.00-1.15 (m, 9H)；LC/MS(ESI+)m/z 552.8(M+H)+。
Example 39
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- Ji Jia
Base)-amino] -5- phenyl -1- ((S)-ttetrahydro-pyran -2- carbonyl)-pyrrolidines -2- Ethyl formate example 38D (23mg,
0.04mmol, 1.0 equivalents) (120 μ L, 0.12mmol, 3.0 work as with LiOH 1.0M in water for solution in methanol (1mL)
Amount) processing, and mixture is stirred overnight at 45 DEG C.After completion of the reaction, the aqueous HCl of 1N is added, and under vacuum by solvent
Removal.Residue is purified on silica gel (methylene chloride/methanol 100/0 to 95/5).Product fraction is merged, and dense
It is reduced to dry to provide title compound (12mg, 54%).1H NMR (400MHz, CDCl3- d) δ ppm 7.29-7.43 (m, 4H),
7.17 (d, J=7.2Hz, 2H), 6.83 (d, J=7.3Hz, 1H), 5.17 (s, 1H), 4.59 (dd, J=10.6,2.0Hz, 1H),
4.07 (dd, J=10.2,2.7Hz, 1H), 3.87 (d, J=13.7Hz, 1H), 3.74 (td, J=11.2,2.3Hz, 1H), 3.50
(s, 1H), 3.33-3.47 (m, 4H), 2.39 (s, 1H), 1.45-1.94 (m, 7H), 1.24-1.35 (m, 9H), 1.01-1.14
(m, 9H)；LC/MS(ESI+)m/z 552.8(M+H)+。
Example 40
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid
Example 40A
(2S, 3R, 4S, 5S)-tert-butyl 1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- (2- methoxyl group
Pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters
At 25 DEG C, by core 39 (0.55g, 1.391mmol) and triethylamine (0.388mL, 2.78mmol) in methylene chloride
Solution in (6.32mL) is handled dropwise with cyclohexanecarbonyl chloride (0.233mL, 1.739mmol).It stirs the mixture for 2 hours,
And with being saturated aqueous NaHCO3(3mL) and 1N NH4The washing of OH (1mL) aqueous solution.Mixture is concentrated.Rough material is dissolved in 1mL
In methylene chloride and it is loaded on 12g column, it is titled to provide with gradient elution 20 minutes of 0-70% ethyl acetate/heptane
Close object (2S, 3R, 4S, 5S)-tert-butyl 1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- (2- methoxypyridine -
3- yl) -4- nitro-pyrrole alkane -2- formic acid esters (609mg, 1.205mmol, 87% yield).1(400MHz, dimethyl are sub- by HNMR
Sulfone-d6) δ ppm 8.05 (d, J=5.0Hz, 1H), 7.99 (s, 1H), 6.90 (d, J=6.2Hz, 1H), 5.64 (s, 1H),
5.58-5.49 (m, 1H), 4.67 (d, J=3.3Hz, 1H), 3.93 (s, 3H), 3.23 (t, J=2.9Hz, 1H), 3.16 (s,
3H), 2.18 (bs, 1H), 1.69 (d, J=16.3Hz, 2H), 1.51 (s, 11H), 1.25 (d, J=14.5Hz, 8H), 1.20-
1.06 (m, 3H), 0.91-0.78 (m, 1H)；MS(APCI+)m/z 506(M+H)+。
Example 40B
(2S, 3S, 4S, 5S)-tert-butyl 4- amino -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- (2-
Methoxypyridine -3- base) pyrrolidines -2- formic acid esters
In 250mL SS pressure bottle, under argon gas, to example 40A (400mg, 0.791mmol) in tetrahydrofuran
It is added in solution in (12.000mL)2800 aqueous slurry of nickel (555mg, 4.26mmol), and by mixture in 50psi
Hydrogen under oscillation and 50 DEG C at heat 16 hours.Reaction is filtered, and solvent is removed in a vacuum and is loaded into 12g column
On, with gradient elution 20 minutes of 0-9% ethanol/methylene, to provide title compound (2S, 3S, 4S, 5S)-tert-butyl
4- amino -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- first
Acid esters (330mg, 0.694mmol, 88% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.03 (bs, 2H),
6.92 (s, 1H), 5.22 (s, 1H), 4.39 (s, 1H), 3.93 (s, 3H), 3.75 (dd, J=7.4,3.6Hz, 1H), 3.14 (s,
3H), 2.35 (s, 1H), 2.08 (bs, 1H), 1.65 (m, 2H), 1.53 (bs, 2H), 1.46 (s, 9H), 1.38-1.24 (m, 2H),
1.20 (s, 3H), 1.17 (s, 3H), 1.12 (m, 2H), 0.90 (bs, 2H)；MS(ESI+)m/z 476(M+H)+。
Example 40C
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid
To 5- (tert-butyl)-Benzaldehyde,2-methoxy (30.6mg, 0.151mmol), example 40B (60mg, 0.126mmol)
It is with zinc chloride (II) (17.19mg, 0.126mmol) molten in sodium acetate/acetate buffer (pH=4,1mL) in methanol
Sodium cyanoborohydride (11.89mg, 0.189mmol) is added in liquid, and reaction is stirred 2 hours at ambient temperature.By solvent
Removal, and residue is subjected to chromatography using 12g silicagel column, with gradient elution 20 minutes of 0-100% ethyl acetate/heptane,
Providing material (56mg, 0.086mmol, 68.1%), being dissolved in trifluoroacetic acid (0.5mL) and stirring at ambient temperature
24 hours.Solvent is removed, and rough material is purified using trifluoroacetic acid method by reverse phase, with acquisition (2S, 3S, 4S,
5S) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5-
(2- methoxypyridine -3- base) pyrrolidines -2- methanoic acid trifluoro acetate (36mg, 0.051mmol, 40.2% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.10 (d, J=4.9Hz, 2H), 7.23 (dd, J=8.6,2.5Hz, 1H), 7.04
(d, J=2.6Hz, 1H), 6.97 (d, J=6.4Hz, 1H), 6.82 (d, J=8.6Hz, 1H), 5.43 (s, 1H), 4.50 (s,
1H), 3.87 (s, 3H), 3.78 (d, J=13.7Hz, 2H), 3.59 (s, 3H), 3.54 (d, J=13.4Hz, 1H), 3.14 (s,
3H), 2.75 (m, 1H), 2.23 (bs, 1H), 1.74-1.47 (m, 5H), 1.23 (d, J=0.7Hz, 9H), 1.22-1.17 (m,
7H), 1.11 (m, 3H), 0.86 (bs, 1H)；MS(ESI+)m/z 596(M+H)+。
Example 41
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -5-
[2- (dimethylamino) pyridin-3-yl] -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid
Example 41A
(2S, 3R, 4S, 5S)-tert-butyl 1- (cyclohexane carbo) -5- (2- (dimethylamino) pyridin-3-yl) -3- (2-
Methoxy propane -2- base) -4- nitro-pyrrole alkane -2- formic acid esters
At 25 DEG C, by core 38 (0.55g, 1.346mmol) and triethylamine (0.375mL, 2.69mmol) in methylene chloride
Solution in (6.12mL) is handled dropwise with cyclohexanecarbonyl chloride (0.225mL, 1.683mmol), is stirred 2 hours, full with washing
With aqueous NaHCO3(3mL) and 1N NH4The washing of OH (1mL) aqueous solution, is concentrated to provide residue.Rough material is dissolved in 1mL bis-
It in chloromethanes and is loaded on 12g silicagel column, with gradient elution 20 minutes of 0-70% ethyl acetate/heptane, is wished with providing
The product (2S, 3R, 4S, 5S) of prestige-tert-butyl 1- (cyclohexane carbo) -5- (2- (dimethylamino) pyridin-3-yl) -3- (2-
Methoxy propane -2- base) -4- nitro-pyrrole alkane -2- formic acid esters (656mg, 1.265mmol, 94% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.24-8.14 (m, 1H), 8.01 (s, 1H), 6.94 (dd, J=7.7,4.8Hz,
1H), 5.78 (d, J=8.5Hz, 1H), 5.58 (d, J=8.6Hz, 1H), 4.68 (d, J=3.0Hz, 1H), 3.25 (t, J=
2.6Hz, 1H), 3.17 (s, 3H), 2.80 (s, 6H), 2.12 (bs, 1H), 1.69 (m, 2H), 1.52 (s, 9H), 1.49 (bs,
2H), 1.29 (s, 3H), 1.27 (m, 1H), 1.24 (s, 3H), 1.20 (d, J=4.8Hz, 2H), 1.12 (m, 2H), 0.90-0.82
(m, 1H)；MS(APCI+)m/z 519(M+H)+。
Example 41B
(2S, 3S, 4S, 5S)-tert-butyl 4- amino -1- (cyclohexane carbo) -5- (2- (dimethylamino) pyridine -3-
Base) -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid esters
In 250mL SS pressure bottle, to example 41A (400mg, 0.771mmol) in tetrahydrofuran (11.700mL)
It is added in solution2800 aqueous slurry of nickel (550mg, 4.59mmol), with argon cleaning 4 times, with hydrogen (4.66mg,
It 2.314mmol) rinses, and the shaken overnight at room temperature under the hydrogen of 50psi.Reaction mixture is filtered, and solvent is existed
It is removed in vacuum.Rough material is purified using 12g silicagel column, is divided with the gradient elution 20 of 0-9% ethanol/methylene
Clock, to provide title compound (2S, 3S, 4S, 5S)-tert-butyl 4- amino -1- (cyclohexane carbo) -5- (2- (dimethylamino)
Pyridin-3-yl) -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid esters (334mg, 0.683mmol, 89% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.16 (d, J=4.6Hz, 2H), 6.95 (dd, J=7.7,4.8Hz, 1H),
5.36 (d, J=7.1Hz, 1H), 4.37 (d, J=3.8Hz, 1H), 3.84 (s, 1H), 3.16 (s, 3H), 2.81 (s, 6H), 2.38
(t, J=3.6Hz, 1H), 195 (bs, 1H), 1.66 (m, 1H), 1.58 (m, 1H), 1.46 (bs, 12H), 1.31 (m, 1H), 1.21
(s, 3H), 1.20 (s, 3H), 1.06 (bs, 4H)；MS(ESI+)m/z 489(M+H)+。
Example 41C
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -5-
[2- (dimethylamino) pyridin-3-yl] -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid
To 5- (tert-butyl)-Benzaldehyde,2-methoxy (29.8mg, 0.147mmol), example 41B (60mg, 0.123mmol)
It is with zinc chloride (II) (16.73mg, 0.123mmol) molten in sodium acetate/acetate buffer (pH=4,1mL) in methanol
Sodium cyanoborohydride (11.57mg, 0.184mmol) is added in liquid, and reaction is stirred 2 hours at ambient temperature.By solvent
Removal, and gained rough material is subjected to chromatography using 12g silicagel column, divided with the gradient elution 20 of 0-70% ethyl acetate/heptane
Clock is dissolved in trifluoroacetic acid (0.5mL) and at ambient temperature with providing residue (74mg, 0.111mmol, 91%)
Stirring 24 hours.Solvent is removed, and rough material is purified using trifluoroacetic acid method by RP chromatography, to provide
(2S, 3S, 4S, 5S) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (cyclohexane carbo) -5- (2- (dimethylamino
Base) pyridin-3-yl) 2 trifluoroacetate of -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid (69mg, 0.082mmol,
67.2% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.20 (dd, J=4.8,1.8Hz, 1H), 8.10 (s,
1H), 7.20 (dd, J=8.5,2.6Hz, 1H), 7.06 (d, J=2.5Hz, 1H), 7.00 (dd, J=7.7,4.8Hz, 1H),
6.78 (d, J=8.6Hz, 1H), 5.48 (d, J=6.6Hz, 1H), 4.62 (d, J=1.9Hz, 1H), 3.81 (d, J=13.6Hz,
1H), 3.73 (d, J=6.7Hz, 1H), 3.52 (s, 3H), 3.46 (d, J=13.7Hz, 1H), 3.17 (d, J=1.0Hz, 3H),
2.74 (s, 1H), 2.69 (d, J=1.0Hz, 6H), 2.10 (bs, 1H), 1.70-1.43 (m, 4H), 1.25 (s, 3H), 1.21 (d,
J=0.9Hz, 13H), 1.06 (d, J=11.7Hz, 3H), 0.85 (bs, 1H)；MS(ESI+)m/z 609(M+H)+。
Example 42
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid
Example 42A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (3,3- difluorocyclohex alkyl carbonyl) -5- (2- (dimethylamino)
Pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters
To 3,3- difluorocyclohex alkane formic acid [CAS# 849669-20-1] (393mg, 2.395mmol) and a few drop N, N- diformazan
Base formamide adds oxalyl dichloro in methylene chloride (8mL) (760mg, 5.99mmol, 3mL, 2M are in methylene chloride).It will mix
It closes object to stir at ambient temperature 30 minutes, solvent is removed under stress, fresh methylene chloride (5mL) is added and goes again
It removes.Residue is dissolved in methylene chloride (2mL) and is added dropwise to (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (diformazan
Base amino) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters (core 11,728mg, 2.0mmol) dichloro cooling in ice bath
In solution in methane (10mL).Mixture is stirred 1 hour at ambient temperature, is washed with brine and through MgSO4It is dry.It crosses
After filter, solvent is removed, and residue is purified on 40g silicagel column via chromatography, the ethyl acetate in heptane with
The gradient elution of 0-40%, with offer (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (3,3- difluorocyclohex alkyl carbonyl) -5-
(2- (dimethylamino) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters 655mg (64.3% yield), is directly used in
In next step.LC/MS(APCI+)m/z 511(M+H)+。
Example 42B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (3,3- difluorocyclohex alkyl carbonyl) -5- (2- (diformazan
Base amino) pyridin-3-yl) pyrrolidines -2- formic acid esters
Replace example 10B with example 42A, title compound is prepared according to program described in example 10C.LC/MS(APCI
+)m/z 447.3(M+H)+。
Example 42C
(2S, 3S, 4S, 5S)-methyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1-
((S) -3,3- difluorocyclohex alkyl carbonyl) -5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -2- formic acid esters
With
Example 42D
(2S, 3S, 4S, 5S)-methyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1-
((R) -3,3- difluorocyclohex alkyl carbonyl) -5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -2- formic acid esters
By 5- (tert-butyl)-Benzaldehyde,2-methoxy [CAS# PH011292] (80mg, 0.416mmol), example 42B
(200mg, 0.416mmol) and zinc chloride (II) (11.34mg, 0.083mmol) are sodium acetate/acetate buffer in methanol
Mixture in (pH=4,2mL) stirs 10 minutes at ambient temperature, add later sodium cyanoborohydride (39.2mg,
0.624mmol).It stirs the mixture for 1 hour, and solvent is removed under stress.By residue via color on 40g silicagel column
Spectrometry purifying, the ethyl acetate/methanol (10: 1) in heptane is eluted with 0-40%, to obtain the elution as example 42C
The first compound (105mg, 38.4% yield).LC/MS(APCI+)m/z 657.62(M+H)+.The second compound of elution
It is example 42D 110mg (40.2% yield).LC/MS(APCI+)m/z 657.67(M+H)+。
Example 42E
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (5- (tert-butyl) -2- Methoxybenzamido) -1- ((R) -3,
3- difluorocyclohex alkyl carbonyl) -5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -2- formic acid
By the mixture of example 42D (105mg, 0.163mmol) and 6M LiOH (0.5mL) in methanol (2mL) at 50 DEG C
Lower stirring 3 hours.PH is adjusted to 4-5 by the 4M HCl in dioxanes.Solvent is removed under stress, and residue is existed
It is purified on 12g silicagel column via chromatography, it is titled to provide with methanol in methylene chloride with the gradient elution of 0-20%
It closes object 93mg (91% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.19 (s, 2H), 7.12 (dd, J=8.5,
2.6Hz, 1H), 6.99 (t, J=2.8Hz, 2H), 6.71 (dd, J=8.5,1.5Hz, 1H), 5.40 (t, J=5.9Hz, 1H),
4.55 (s, 1H), 3.70-3.62 (m, 1H), 3.52 (d, J=5.5Hz, 1H), 3.43 (d, J=1.3Hz, 3H), 3.29 (d, J=
13.8Hz, 1H), 3.19 (s, 1H), 2.64 (s, 1H), 2.60 (s, 6H), 2.43 (s, 1H), 1.54 (s, 6H), 1.25 (s, 2H),
1.19 (s, 9H), 1.01 (s, 9H)；MS(ESI+)m/z 629.2(M+H)+。
Example 43
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*) -3,4- dihydro -2H-1- chromene -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- first
Acid
Example 43A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (benzodihydropyran -2- carbonyl) -5- (2- (dimethylamino
Base) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid esters
By benzodihydropyran -2- formic acid (0.587g, 3.29mmol) and 1- chloro- N, N, 2- trimethyl propyl- 1- alkene -1- amine
The mixture of (Ghosez solvent, 0.726mL, 5.49mmol) in methylene chloride (20mL) stirs 10 points at ambient temperature
Clock.Add (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- in pyridine
Nitro-pyrrole alkane -2- formic acid esters (core 11,1g, 2.74mmol).Mixture is stirred at ambient temperature 1 hour.Add dichloro
Methane (10mL), and organic layer is washed with brine and through MgSO4It is dried, filtered and concentrated.By residue on 24g silicagel column
It is purified via chromatography, the ethyl acetate in heptane is with the gradient elution of 0-40%, to provide title compound, 961mg
(67% yield).LC/MS(APCI+)m/z 525(M+H)+。
Example 43B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (benzodihydropyran -2- carbonyl) -5- (2- (two
Methylamino) pyridin-3-yl) pyrrolidines -2- formic acid esters
It will be added in 50mL pressure bottle in the example 43A (960mg, 1.830mmol) in tetrahydrofuran (30mL)In 2800 aqueous slurry of nickel (3g, 23.00mmol).Mixture is stirred 16 hours at 50 DEG C, is rushed with 50psi hydrogen
It washes, then filter and is concentrated, to provide title compound 900mg (99% yield).LC/MS(APCI+)m/z 495.35(M+H)+。
Example 43C
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- ((S*)-benzodihydropyran -2- carbonyl) -5-
(2- (dimethylamino) pyridin-3-yl) pyrrolidines -2- formic acid esters
With
Example 43D
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- ((R*)-benzodihydropyran -2- carbonyl) -5-
(2- (dimethylamino) pyridin-3-yl) pyrrolidines -2- formic acid esters
The diastereoisomer of example 43B (960mg, 1.94mmol) is separated into [method: 10_29_100_ via HPLC
CH3CN_ trifluoroacetic acid _ 120mL_11 minutes；Injection volume: 1500 μ L；Mobile phase: CAN/ trifluoroacetic acid；Column: Waters
SunfireTMPrep C8 OBD 10um 50x150mm], with the first examples of compounds 43C 340mg eluted
(35.4% yield).Acquisition time: 6.66-7.35 minutes.LC/MS(APCI+)m/z 459.3(M+H)+.The second of elution changes
Closing object is example 43D (350mg, 36.5% yield).Acquisition time: 7.41-8.32 minutes.LC/MS(APCI+)m/z 459.3
(M+H)+。
Example 43E
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(5- tert-butyl -2- methoxyl group-phenyl) methylamino] -1- [(2S*) -
Benzodihydropyran -2- carbonyl] -5- [2- (dimethylamino) -3- pyridyl group] pyrrolidines -2- formic acid
By 5- (tert-butyl)-Benzaldehyde,2-methoxy (23.32mg, 0.121mmol), example 43C (60mg,
0.121mmol) and zinc chloride (II) (3.31mg, 0.024mmol) be in methanol sodium acetate/acetate buffer (pH=4,
Mixture in 2mL) stirs 10 minutes at ambient temperature, to provide colourless solution.Addition sodium cyanoborohydride (11.43mg,
0.182mmol), it and stirs the mixture for 1 hour.Solvent is removed under stress, is added methylene chloride (10mL), by mixture
It filters, and is concentrated on 10g silicagel column.Residue is dissolved in methanol (1.5mL) and the aqueous LiOH of 4M (0.5mL).It will mixing
Object stirs 3 hours at 50 DEG C, pH is adjusted to 4-5 by adding the 4M HCl in dioxanes, and mixture is concentrated.It will
Residue is dissolved in methylene chloride (1mL), is filtered by syringe, and is purified on 4g silicagel column via chromatography, is used in two
Methanol in chloromethanes is with the gradient elution of 0-20%, to obtain title compound 39mg (50.0% yield).1H NMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.17 (d, J=4.6Hz, 1H), 7.12 (dd, J=8.5,2.5Hz, 1H), 7.06-
6.92 (m, 5H), 6.79-6.67 (m, 3H), 5.64 (s, 1H), 4.64 (s, 1H), 3.64 (d, J=13.7Hz, 1H), 3.56 (d,
J=6.7Hz, 1H), 3.46 (s, 3H), 3.28 (d, J=13.7Hz, 1H), 3.19 (s, 1H), 2.64 (d, J=14.7Hz, 3H),
2.55 (s, 6H), 2.44 (s, 1H), 1.81 (s, 2H), 1.19 (s, 9H), 1.02 (s, 9H)；MS(ESI+)m/z 643.2(M+H)+。
Example 44
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(1S*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid
Replace example 42D with example 42C, title compound is prepared according to program described in example 42E.1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.20 (d, J=5.4Hz, 2H), 7.13 (dt, J=8.6,2.5Hz, 1H), 6.99
(t, J=3.1Hz, 2H), 6.73-6.68 (m, 1H), 5.40 (t, J=5.9Hz, 1H), 4.53 (d, J=14.8Hz, 1H), 3.65
(dd, J=13.8,7.1Hz, 2H), 3.53 (d, J=6.0Hz, 1H), 3.44 (d, J=1.0Hz, 3H), 3.30 (dd, J=
13.8,4.7Hz, 2H), 2.64 (s, 1H), 2.60 (d, J=1.1Hz, 6H), 2.43 (s, 1H), 1.85-1.46 (m, 6H), 1.25
(s, 2H), 1.19 (s, 9H), 1.01 (s, 9H)；MS(ESI+)m/z 629.2(M+H)+。
Example 45
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 45A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoro-methoxy) phenyl) -4- nitro -1- ((S)-four
Hydrogen -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
With
Example 45B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (difluoro-methoxy) phenyl) -4- nitro -1- ((R)-four
Hydrogen -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
By tetrahydro -2H- pyrans -2- formic acid [CAS# 51673-83-7] (323mg, 2.485mmol) and 1- chloro- N, N, 2-
Mixture of the trimethyl propyl- 1- alkene -1- amine (Ghosez reagent, 0.548mL, 4.14mmol) in methylene chloride (30mL) is in ring
It is stirred 10 minutes at a temperature of border.The core 15 (800mg, 2.07mmol) in pyridine/tetrahydrofuran (1: Isosorbide-5-Nitrae mL) is added, and will
Mixture stirs 1 hour.Mixture is washed with brine, through MgSO4It is dried, filtered and concentrated.By residue in 80g silicagel column
On purified via chromatography, the ethyl acetate in heptane with the gradient elution of 0-40%, with obtain example 45A (520mg,
50.4% yield), the first compound as elution.LC/MS(APCI+)m/z 499.42(M+H)+.Have also obtained example 45B
(350mg, 33.9% yield), the second compound as elution.LC/MS(APCI+)m/z 499.29(M+H)+。
Example 45C
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- (difluoro-methoxy) phenyl) -1- ((R)-four
Hydrogen -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Replace example 36B with example 45B, title compound is prepared according to program described in example 36C.MS(ESI+)m/
z 469.1(M+H)+。
Example 45D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(5- tert-butyl -2- methoxyl group-phenyl) methylamino] -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(2R)-oxinane -2- carbonyl] pyrrolidines -2- formic acid
By 5- (tert-butyl)-Benzaldehyde,2-methoxy (24.62mg, 0.128mmol), example 45C (60mg,
0.128mmol) and zinc chloride (II) (3.49mg, 0.026mmol) be in methanol sodium acetate/acetate buffer (pH=4,
Mixture in 2mL) stirs 10 minutes at ambient temperature.It adds sodium cyanoborohydride (12.07mg, 0.192mmol), will mix
It closes object to be stirred for 1 hour, and adds methylene chloride (10mL).Organic layer is washed with brine, through MgSO4It dries, filters, and
Concentration.Residue is purified on 12g silicagel column via chromatography, the ethyl acetate/methanol (10: 1) in heptane is with 0-
40% gradient elution, to obtain (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxybenzyl
Base) amino) -5- (2- (difluoro-methoxy) phenyl) -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters, it will
It is dissolved in methanol (1.5mL) and the aqueous LiOH of 4M (0.5mL).Mixture is stirred 3 hours at 50 DEG C, pH is adjusted to 4-
5, and mixture is concentrated.Residue is dissolved in methylene chloride (2mL) and is filtered by syringe type filter.By rough material
It is purified on 4g silicagel column via chromatography, with methanol in methylene chloride with the gradient elution of 0-20%, to provide title
Compound, 44mg (55.7% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.69 (s, 1H), 7.35 (m, 1H),
7.24-7.10 (m, 3H), 7.03 (m, 1H), 6.8 (m, 1H), 5.41 (s, 1H), 4.91 (s, 1H), 4.14 (s, 1H), 3.90 (s,
1H), 3.64 (s, 2H), 3.54 (d, J=25.9Hz, 3H), 3.48 (m, 2H), 3.37 (m, 1H), 2.46 (q, J=2.0Hz,
1H), 1.68-1.42 (m, 6H), 1.26 (s, 9H), 1.05 (s, 9H)；MS(ESI+)m/z 617.2(M+H)+。
Example 46
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- first
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid
Example 46A
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- (5- tert-butyl -2- methoxy
Base-benzylamino) -5- phenyl-pyrrolidin -2- Ethyl formate
At 0 DEG C, Xiang Erhuan [3.1.0] hexane -6- formic acid (28mg, 0.22mmol, 1.3 equivalent) is in methylene chloride
In agitating solution in (1mL) add Ghosez ' s reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, 67 μ L, 0.51mmol,
3.0 equivalents).Reaction mixture is stirred 5 minutes at 0 DEG C, and adds (2S, 3S, 4S, 5S) -3- tert-butyl -4- (tertiary fourth of 5-
Base -2- Methoxy-benzylamino) -5- phenyl-pyrrolidin -2- Ethyl formate (example 34D, 80mg, 0.17mmol, 1.0 equivalent)
With solution of the diisopropylethylamine (118 μ L, 0.68mmol, 4.0 equivalent) in methylene chloride (1mL).By reaction mixture 0
It stirs 10 minutes and is stirred at room temperature 72 hours at DEG C.Reaction mixture is washed with water, and organic phase is concentrated to dryness.It will
Residue by purified by flash chromatography (heptane/ethyl acetate 100/0 to 85/15), with provide title compound (60mg,
61%).LC/MS(ESI+)m/z 575.9(M+H)+。
Example 46B
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- (5- tert-butyl -2- methoxy
Base-benzylamino) -5- phenyl-pyrrolidin -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- (uncle 5-
Butyl -2- Methoxy-benzylamino) -5- phenyl-pyrrolidin -2- Ethyl formate (60mg, 0.10mmol, 1.0 equivalent) is in methanol
LiOH 1.0M (300 μ L, 0.30mmol, the 3.0 equivalent) processing of solution in water in (2mL), and it is stirred at 45 DEG C
Night.Aqueous 1N HCl is added, and solvent is removed under vacuum.Residue is purified into (dichloromethane by flashchromatography on silica gel
Alkane/methanol 100/0 to 92/8), to provide title compound (38mg, 70%).1H NMR (400MHz, CDCl3)δppm
7.26-7.47 (m, 5H), 7.08 (d, J=2.2Hz, 2H), 6.58-6.71 (m, 1H), 5.21 (d, J=6.1Hz, 1H), 4.80
(s, 1H), 4.01-4.15 (m, 1H), 3.55 (d, J=14.0Hz, 1H), 3.51 (s, 1H), 3.32 (d, J=6.3Hz, 1H),
3.19-3.29 (m, 4H), 2.44 (s, 1H), 2.21 (t, J=2.9Hz, 1H), 1.84-2.06 (m, 2H), 1.62-1.82 (m,
3H), 1.33-1.46 (m, 1H), 1.19-1.31 (m, 9H), 0.97-1.09 (m, 9H)；LC/MS(ESI+)m/z 547.8(M+H)+。
Example 47
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trimethyl silyl
Base) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 47A
(2S, 3S, 4S, 5S) -3- tert-butyl -1- cyclohexane carbo -4- [(2- methoxyl group -5- trimethylsilyl-pyridine -
3- ylmethyl)-amino] -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (10mg, 0.15mmol, 1.3 equivalent) be added to example 7B (50mg, 0.12mmol, 1.0 equivalent) and
2- methoxyl group -5- trimethylsilyl-pyridine -3- formaldehyde (31mg, 0.14mmol, 1.2 equivalent) is in acetic acid/sodium acetate/methanol
In solution in buffer (2mL).Reaction mixture is stirred at room temperature 30 minutes.Reaction mixture is concentrated, and will be residual
Excess is in methylene chloride and aqueous NaHCO3Between distribute.By organic phase in Na2SO4On be dried, filtered and concentrated.By residue
(dichloromethane/ethyl acetate 100/0 to 95/5) is purified on silica gel, and to provide title compound, (55mg, 74% is obtained
Rate).LC/MS(ESI+)m/z 594.0(M+H)+。
Example 47D
(2S, 3S, 4S, 5S) -3- tert-butyl -1- cyclohexane carbo -4- [(2- methoxyl group -5- trimethylsilyl-pyridine -
3- ylmethyl)-amino] -5- phenyl-pyrrolidin -2- formic acid
LiOH (19mg, 0.45mmol, 5.0 equivalent) is added to (2S, 3S, 4S, 5S) -3- tert-butyl -1- hexamethylene carbonyl
Base -4- [(2- methoxyl group -5- trimethylsilyl-pyridin-3-yl methyl)-amino] -5- phenyl-pyrrolidin -2- Ethyl formate
(55mg, 0.09mmol, 1.0 equivalent) is in the solution in tetrahydrofuran/methanol/water (1.5/1.5/1).By the reaction mixture
It is stirred overnight at 45 DEG C.Reaction mixture is acidified with aqueous HCl 1M (1 equivalent/LiOH).Mixture is concentrated and uses dichloro
Methane extraction.Organic phase is concentrated.Residue is purified on silica gel (methylene chloride/methanol 100/0 to 95/5), with
Provide title compound (50mg, 96% yield).1H NMR (400MHz, CDCl3) δ ppm 8.18 (d, J=1.5Hz, 1H),
7.27-7.52 (m, 4H), 7.17 (d, J=5.5Hz, 2H), 5.26 (d, J=6.1Hz, 1H), 4.67 (s, 1H), 3.94 (d, J=
14.0Hz, 1H), 3.52 (d, J=14.0Hz, 1H), 3.46 (s, 3H), 3.29 (d, J=6.1Hz, 1H), 2.85-3.04 (m,
1H), 2.39 (s, 1H), 1.59-1.90 (m, 6H), 1.10-1.55 (m, 4H), 0.88-1.10 (m, 9H), 0.07-0.28 (m,
9H)；LC/MS(ESI+)m/z 566.5(M+H)+。
Example 48
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -5- methoxypyridine -4- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid
Example 48A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((2- (tert-butyl) -5- methoxypyridine -4- base) methyl)
Amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters
By the different cigarette aldehyde (0.040g, 0.207mmol) of 2- (tert-butyl) -5- methoxyl group and (2S, 3S, 4S, 5S)-ethyl 4- ammonia
Base -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters (example 7B, 0.083g, 0.207mmol) is mixed
Together in methanol (2mL), and reaction is stirred at room temperature 1 hour.Then disposably addition sodium cyanoborohydride (0.065g,
1.035mmol), and by reaction continue to be stirred at room temperature overnight.After this, methanol is evaporated in vacuo, and by residue
It is absorbed in CH2Cl2In water, and it is transferred on separatory funnel.These are mutually separated, and water layer is used into CH again2Cl2It is extracted twice.
By combined organic matter through Na2SO4It dries, filters, and is concentrated in a vacuum.Make thick title compound without further purification i.e.
Into in next step reaction.MS(APCI+)m/z 578.6(M+H)+。
Example 48B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -5- methoxypyridine -4- base) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid
By example 48A (0.120g, 0.207mmol) and lithium hydroxide (1M is aqueous) (1.7mL, 1.7mmol) in tetrahydro furan
Mutter (1.7mL) and methanol (1.7mL) in stirred 2 hours at 45 DEG C.Mixture is cooled to room temperature and uses the aqueous HCl acidification of 1N
To pH 1.Mixture is concentrated in a vacuum, and crude product is existed by reversed-phase HPLCC8(2)5umIt is purified on AXIA column (30mm × 75mm).The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water,
Flow velocity is 50mL/ minutes (0-1.0 minutes 5%A, 1.0-8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minutes 100%
A, 11.5-12.0 minutes linear gradient 95%-5%A), to provide title compound (0.0356g, 31% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.08 (s, 1H), 7.59 (m, 2H), 7.35-7.24 (m, 3H), 7.06 (s, 1H),
5.25 (m, 1H), 4.49 (d, J=2.4Hz, 1H), 3.71 (s, 3H), 3.65-3.54 (m, 2H), 3.38 (m, 1H), 2.38 (m,
1H), 2.24 (m, 1H), 1.65-1.02 (m, 9H), 1.25 (s, 9H), 0.98 (s, 9H), 0.77 (m, 1H)；MS(ESI+)m/z
550.3(M+H)+。
Example 49
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 49A
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (the fluoro- cyclohexane carbo of (R) -3,3- bis-) -4- [(2- methoxyl group -5- three
Methyl fluoride-pyridin-3-yl methyl)-amino] -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (6mg, 0.12mmol, 1.3 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1-
(the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate (example 31B, 31mg, 0.07mmol, 1.0
Equivalent) and 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (17mg, 0.085mmol, 1.2 equivalent) it is slow in acetic acid/sodium acetate/methanol
In solution in fliud flushing (2mL).The solution is stirred at room temperature 30 minutes.Reaction mixture is concentrated, and residue is existed
It is distributed between methylene chloride and water.By organic phase in Na2SO4On be dried, filtered and concentrated.Residue is passed through into silica gel chromatography
Purifying (dichloromethane/ethyl acetate 100/0 to 95/5) is used in next step with providing title compound.LC/MS
(ESI+)m/z 626.5(M+H)+。
Example 49B
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (the fluoro- cyclohexane carbo of (R) -3,3- bis-) -4- [(2- methoxyl group -5- three
Methyl fluoride-pyridin-3-yl methyl)-amino] -5- phenyl-pyrrolidin -2- formic acid
LiOH (15mg, 0.35mmol, 5.0 equivalent) is added to (2S, 3S, 4S, 5S) -3- tert-butyl -1- ((R) -3,3-
Two fluoro- cyclohexane carbos) -4- [(2- methoxyl group -5- trifluoromethylpyridin -3- ylmethyl)-amino] -5- phenyl-pyrrolidin -
2- Ethyl formate (31mg, 0.07mmol, 1.0 equivalent) is in the solution in methanol/tetrahydrofuran/water (1.5/1.5/1).It should
Reaction mixture is stirred overnight at 45 DEG C.Reaction mixture is acidified with aqueous HCl 1M (1 equivalent/LiOH).Mixture is dense
It contracts and is extracted with dichloromethane.Organic phase is concentrated.Residue is purified by silica gel chromatography (methylene chloride/methanol 100/0
To 95/5), to provide title compound (through 2 steps, 29mg, 66% yield).1H NMR (300MHz, CDCl3)δppm
8.28-8.45 (m, 1H), 7.59 (br.s., 1H), 7.34-7.52 (m, 3H), 7.19 (d, J=6.5Hz, 2H), 5.31 (d, J=
5.9Hz, 2H), 4.62-4.75 (m, 1H), 3.92 (d, J=14.1Hz, 1H), 3.69-3.81 (m, 3H), 3.60-3.65 (m,
3H), 3.35 (d, J=5.9Hz, 2H), 2.35-2.60 (m, 1H), 2.05-2.28 (m, 1H), 1.20-2.01 (m, 4H), 0.97-
1.17 (m, 9H)；LCJMS(ESI+)m/z 598.5(M+H)+。
Example 50
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorine
Phenyl) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 50A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -5- (2- fluorophenyl) -4- nitro -1- ((R)-tetrahydro -2H- pyrans -
2- carbonyl) pyrrolidines -2- formic acid esters
Oxinane -2- formic acid (318.1mg, 2.444mmol) is dissolved in methylene chloride (10mL).Add oxalyl chloride
(436.5mg, 3.44mmol) then adds n,N-Dimethylformamide (25 μ L).Reaction is stirred at room temperature 3 hours, at this time
It is concentrated, is re-dissolved in methylene chloride (1mL) and is concentrated again.Residue is absorbed in methylene chloride (3x1mL), and
It is added to the solution of core 23 (540.8mg, 1.598mmol) and triethylamine (500 μ L, 3.59mmol) in methylene chloride (10mL)
In.Reaction is stirred 17 hours at ambient temperature.After this, by mixture CH2Cl2(100mL) dilution, and use saturated water
Property NaHCO3It washes twice, and is washed with brine primary.By organic layer through Na2SO4It is dried, filtered and concentrated.Residue is passed through
Silica gel chromatography (5% to 40% ethyl acetate in heptane).Title compound is the diastereo-isomerism of the second elution
Body (212.8mg, 30%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.73-7.61 (m, 1H), 7.31-
7.22 (m, 1H), 7.06 (dd, J=10.1,8.2Hz, 2H), 5.81 (s, 1H), 5.51 (dd, J=8.8,2.5Hz, 1H), 5.11
(s, 1H), 4.29 (q, J=7.1Hz, 2H), 3.79 (s, 1H), 3.33 (s, 1H), 1.95 (s, 1H), 1.78 (s, 1H), 1.50
(d, J=52.5Hz, 4H), 1.29 (t, J=3.8Hz, 3H), 1.26 (d, J=2.4Hz, 2H), 1.02 (s, 9H)；MS(ESI+)
m/z 451(M+H)+。
Example 50B
Ethyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -5- (2- fluorophenyl) -1- ((R)-tetrahydro -2H- pyrans -
2- carbonyl) pyrrolidines -2- formic acid esters
Example 50A (212.8mg, 0.472mmol) and tetrahydrofuran (4mL) are added in 20mL pressure bottleIn 2800 aqueous slurry of nickel (475mg, 3.64mmol), and mixture is vibrated 16 at 50psi H2 and environment temperature
Hour.Reaction is filtered and is concentrated to provide title compound (196mg, 99%).1HNMR (400MHz, dimethyl sulfoxide-d6,
120 DEG C) δ ppm 7.77-7.65 (m, 1H), 7.30-7.19 (m, 1H), 7.14-7.01 (m, 2H), 5.30 (d, J=6.9Hz,
1H), 4.20 (q, J=7.1Hz, 2H), 3.83 (d, J=47.7Hz, 2H), 3.72-3.64 (m, 1H), 2.13 (s, 1H), 1.83-
1.71 (m, 2H), 1.37 (s, 6H), 1.25 (t, J=7.1Hz, 3H), 0.99 (d, J=1.7Hz, 9H)；MS(ESI+)m/z 421
(M+H)+。
Example 50C
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2-
Fluorophenyl) -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
By example 50B (51.0mg, 0.121mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (54.7mg,
It 0.285mmol) is dissolved in methanol (1mL), and stirs 1 hour at ambient temperature.Addition sodium cyanoborohydride (54.7mg,
0.870mmol), and by reaction it is stirred at ambient temperature 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filtering
And purified using ammonium acetate method by RP chromatography, to provide title compound (47.2mg, 65%).1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.67 (s, 1H), 7.24 (d, J=8.5Hz, 1H), 7.11 (dd, J=
8.5,2.6Hz, 1H), 7.05 (t, J=9.7Hz, 2H), 6.91 (d, J=2.6Hz, 1H), 6.72 (d, J=8.5Hz, 1H),
5.36 (s, 1H), 4.89 (s, 1H), 4.14 (qd, J=7.1,1.8Hz, 2H), 3.88 (d, J=50.1Hz, 2H), 3.51 (s,
3H), 3.49-3.39 (m, 3H), 3.32 (d, J=13.5Hz, 1H), 2.46-2.46 (m, 1H), 1.79 (s, 1H), 1.67-1.36
(m, 5H), 1.19 (s, 12H), 0.98 (s, 9H)；MS(ESI+)m/z 597(M+H)+。
Example 50D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorine
Phenyl) -1- [(2R)-oxane -2- carbonyl]
Pyrrolidines -2- formic acid
Example 50C (44.2mg, 0.074mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in trifluoroacetate
Title compound (40.0mg, 79%).1H NMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.65 (s, 1H),
7.34-7.23 (m, 1H), 7.20 (dd, J=8.6,2.6Hz, 1H), 7.12 (q, J=8.6,8.0Hz, 2H), 7.02 (d, J=
2.5Hz, 1H), 6.79 (d, J=8.6Hz, 1H), 5.43 (d, J=6.9Hz, 1H), 4.87 (s, 1H), 4.03 (s, 1H), 3.84
(s, 2H), 3.73 (d, J=13.7Hz, 1H), 3.64 (d, J=7.0Hz, 1H), 3.57 (s, 3H), 3.49-3.41 (m, 1H),
2.56 (s, 1H), 1.79 (s, 1H), 1.61-1.39 (m, 5H), 1.21 (s, 9H), 0.98 (s, 9H)；MS(ESI+)m/569(M+
H)+。
Example 51
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 51A
5- (two rings [1.1.1] pentane -1- base)-Benzaldehyde,2-hydroxy
By 4- (two rings [1.1.1] pentane -1- base) phenol (266.4mg, 1.663mmol), magnesium chloride (252.6mg,
2.65mmol) and paraformaldehyde (435.5mg, 14.50mmol) be suspended in acetonitrile (8mL), and add triethylamine (1.4mL,
10.04mmol).Gained suspension is vigorously stirred and is heated to 80 DEG C and continues 18 hours, at this time LC/MS show complete conversion for
Desired product.It adds aqueous HCl (1M, 50mL), and reaction is extracted with methylene chloride (2x50mL).By the organic of merging
Layer is through MgSO4It is dried, filtered and concentrated to provide title compound (313.1mg, 100%).1(500MHz, dimethyl are sub- by HNMR
Sulfone-d6) δ ppm 10.61 (s, 1H), 10.22 (s, 1H), 7.42 (d, J=2.3Hz, 1H), 7.35 (dd, J=8.4,2.3Hz,
1H), 6.92 (d, J=8.4Hz, 1H), 2.50 (s, 1H), 2.00 (s, 6H)；MS(ESI+)m/z 187(M+H)+。
Example 51B
5- (two rings [1.1.1] pentane -1- base)-Benzaldehyde,2-methoxy
Example 51A (310.3mg, 1.649mmol) is dissolved in n,N-Dimethylformamide (5mL), and adds potassium carbonate
(347.2mg, 2.51mmol).Gained suspension is vigorously stirred, and adds iodomethane (365.0mg, 2.57mmol).It will suspend
Liquid stirs 20 hours at ambient temperature.It adds aqueous NaOH (1M, 50mL), and by reaction with methyl tertiary butyl ether(MTBE) (2x50mL)
Extraction.Combined extract is washed with water (50mL) and salt water (50mL), it is then dried over magnesium sulfate, filter and be concentrated with to
Title compound (300.5mg, 90%) out.1HNMR (500MHz, dimethyl sulfoxide-d6) δ ppm 10.32 (s, 1H), 7.51-
7.44 (m, 2H), 7.18-7.13 (m, 1H), 3.88 (s, 3H), 2.52 (s, 1H), 2.02 (s, 6H)；MS(ESI+)m/z 203(M
+H)+。
Example 51C
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -1- (four
Hydrogen -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Replace example 50A with the mixture of example 18A and 18B, title compound is prepared according to program described in example 50B
Object.Example 51D
Ethyl (2S, 3S, 4S, 5S) -4- ((5- (two rings [1.1.1] pentane -1- base) -2- methoxy-benzyl) amino) -3-
(tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid
Ester
Example 51C (92.3mg, 0.207mmol) and example 51B (41.3mg, 0.204mmol) are dissolved in methanol (1mL)
And it stirs 1 hour at ambient temperature.It adds sodium cyanoborohydride (69.3mg, 1.103mmol), and will react in environment temperature
Under be stirred for 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filter and is carried out using trifluoroacetic acid method by reverse phase
Purifying.Title compound is the diastereoisomer (43.6mg, 25%) of the first elution as the separation of double trifluoroacetates.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.26 (dd, J=7.5,1.8Hz, 1H), 8.19 (dd, J=4.9,
1.8Hz, 1H), 7.05 (dd, J=7.6,4.9Hz, 1H), 7.00 (dd, J=8.4,2.2Hz, 1H), 6.82 (d, J=2.2Hz,
1H), 6.78 (d, J=8.3Hz, 1H), 5.59 (d, J=6.7Hz, 1H), 4.65 (d, J=1.6Hz, 1H), 4.15 (qq, J=
7.4,3.7Hz, 2H), 3.77-3.70 (m, 3H), 3.67 (d, J=13.6Hz, 1H), 3.59 (s, 3H), 3.29 (d, J=
13.5Hz, 1H), 2.80 (s, 6H), 2.50 (d, J=3.3Hz, 1H), 2.43 (s, 1H), 1.95 (s, 6H), 1.68 (s, 1H),
1.41 (s, 6H), 1.22 (t, J=7.1Hz, 3H), 1.01 (s, 9H)；MS(ESI+)m/z 633(M+H)+。
Example 51E
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 51D (43.6mg, 0.051mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.Reaction mixture is sudden by the addition aqueous HCl of 1M (0.5mL)
It goes out, is diluted with dimethyl sulfoxide (1mL), filter and purified using trifluoroacetic acid method by reverse phase, to provide as washing
Title compounds (33.1mg, 78%) that the first de- compound separates, as double trifluoroacetates.1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) δ ppm 8.20 (d, J=5.4Hz, 2H), 7.08-6.98 (m, 2H), 6.86 (d, J=2.1Hz,
1H), 6.80 (d, J=8.3Hz, 1H), 5.61 (d, J=6.7Hz, 1H), 4.59 (d, J=1.4Hz, 1H), 3.81-3.72 (m,
3H), 3.59 (s, 3H), 3.31 (d, J=13.5Hz, 1H), 2.79 (s, 6H), 2.53-2.48 (m, 4H), 1.95 (s, 6H),
1.74-1.63 (m, 1H), 1.41 (s, 5H), 1.01 (s, 9H)；MS(ESI+)m/z 605(M+H)+。
Example 52
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 52A
Ethyl (2S, 3S, 4S, 5S) -4- ((5- (two rings [1.1.1] pentane -1- base) -2- methoxy-benzyl) amino) -3-
(tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid
Ester
Title compound is the diastereoisomer (49.2mg, 28%) of the second elution in example 51D, and as double three
Fluoroacetate separation.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.17 (dd, J=5.0,1.8Hz, 1H),
8.12 (d, J=7.6Hz, 1H), 7.21 (dd, J=2.1,1.0Hz, 1H), 7.06-6.93 (m, 3H), 5.44 (d, J=6.6Hz,
1H), 4.47 (d, J=0.7Hz, 2H), 4.18 (q, J=7.0Hz, 2H), 3.74 (s, 3H), 3.63-3.55 (m, 2H), 3.53
(s, 3H), 3.28 (d, J=13.6Hz, 1H), 2.76 (s, 6H), 2.50 (d, J=3.4Hz, 3H), 2.00 (s, 6H), 1.95 (s,
6H), 1.80 (s, 1H), 1.47 (d, J=28.9Hz, 6H), 1.22 (t, J=7.1Hz, 3H), 1.02 (s, 9H)；MS(ESI+)m/
z 633(M+H)+。
Example 52B
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 52A (49.2mg, 0.057mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide as double trifluoroacetic acids
The title compound (25.4mg, 53%) of salt separation.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 8.19 (dd,
J=4.9,1.8Hz, 1H), 8.08-7.99 (m, 1H), 7.04-6.96 (m, 2H), 6.83 (d, J=2.2Hz, 1H), 6.77 (d, J
=8.3Hz, 1H), 5.45 (d, J=6.6Hz, 1H), 4.91-4.84 (m, 1H), 3.69 (d, J=13.8Hz, 1H), 3.63 (d, J
=6.7Hz, 1H), 3.54 (s, 3H), 3.32 (d, J=13.6Hz, 1H), 2.86 (s, 1H), 2.74 (s, 6H), 2.59-2.48
(m, 4H), 1.95 (s, 6H), 1.83-1.74 (m, 1H), 1.47 (d, J=19.2Hz, 5H), 1.01 (s, 9H)；MS(ESI+)m/z
605(M+H)+。
Example 53
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 53A
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(6- tert-butyl -2- methoxv-pyridine -3- ylmethyl)-amino] -1-
(the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate
By NaBH3CN (8mg, 0.12mmol, 1.2 equivalent) is added to (2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -1-
(the fluoro- cyclohexane carbo of (R) -3,3- bis-) -5- phenyl-pyrrolidin -2- Ethyl formate (example 31B, 40mg, 0.09mmol, 1.0
Equivalent) and 6- tert-butyl -2- methoxv-pyridine -3- formaldehyde (19mg, 0.1mmol, 1.1 equivalent) in acetic acid/sodium acetate/methanol
In solution in buffer (2mL).Reaction mixture is stirred at room temperature 30 minutes.Mixture is concentrated, and by residue
It is distributed between methylene chloride and water.By organic phase in Na2SO4On be dried, filtered and concentrated.Residue is carried out on silica gel
(dichloromethane/ethyl acetate 100/0 to 97/3) is purified to provide title compound.LC/MS(ESI+)m/z 614.8(M+H)+。
Example 53B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 53A is dissolved in methanol/tetrahydrofuran/water (1.5/1.5/1), and by LiOH (19mg, 0.45mmol, 5.0
Equivalent) it is added in reaction mixture.Solution is stirred overnight at 45 DEG C.By reaction mixture with aqueous HCl 1M (1 equivalent/
LiOH it) is acidified.Mixture is concentrated and is extracted with dichloromethane.Organic phase is concentrated.Residue is pure by silica gel chromatography
Change (methylene chloride/methanol 100/0 to 95/5), to provide title compound (through 2 steps, 30mg, 57% yield).1H NMR
(400MHz, DMSO-d6, 100 DEG C) δ ppm 7.61 (br.s., 2H), 7.26-7.41 (m, 3H), 7.22 (d, J=7.5Hz,
1H), 6.81 (d, J=7.5Hz, 1H), 5.21 (d, J=6.2Hz, 1H), 4.50 (br.s, 1H), 3.68 (br.s., 3H),
3.37-3.57 (m, 2H), 3.24-3.36 (m, 1H), 2.95 (br.s., 1H are under water peaks), 2.33 (br.s., 1H), 1.38-
2.12 (m, 8H), 1.28 (s, 9H), 1.00 (s, 9H)；LC/MS(ESI+)m/z 586.5(M+H)+。
Example 54
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- (2,2,6,6- tetramethyl oxane -4- carbonyl) pyrrolidines -2- formic acid
Example 54A
2,2,6,6- tetramethyl tetrahydro -2H- pyrans -4- formonitrile HCNs
By -4 (3H) -one (3g, 19.20mmol) of 2,2,6,6- tetramethyl dihydro -2H- pyrans and toylsulfonomethylisocyanide
(4.87g, 24.96mmol) is dissolved in dimethoxy-ethane (20mL).After being cooled to -10 DEG C in acetone-ice bath, through 40 minutes
It is added batch-wise potassium tert-butoxide (2.80g, 24.96mmol), is kept for 5 DEG C of temperature <.Reaction mixture is stirred 1 hour at 0 DEG C
Then it stirs 2 hours at ambient temperature.By mixture with diethyl ether (30mL) dilute, and by solid by sinter funnel via
Filtering removal.Filtrate is concentrated, and product is distributed between diethyl ether and water.Combined organic extract is concentrated, and is passed through
By purified by flash chromatography, with 0: 100 to 7: 93 ethyl acetate on 120g silicagel column: heptane elutes 20 minutes, to provide
The title compound of 885mg.1HNMR (500MHz, chloroform-d) δ ppm 2.95 (tt, J=12.7,3.5Hz, 1H), 1.96-
1.85 (m, 2H), 1.67-1.52 (m, 2H), 1.27 (s, 6H), 1.26 (s, 6H)；MS(DCI+)m/z 185.4(M+NH4)+。
Example 54B
2,2,6,6- tetramethyl tetrahydro -2H- pyrans -4- formic acid
Example 54A (700mg, 4.19mmol) is dissolved in ethyl alcohol (14mL).Dropwise addition sodium hydroxide (3M, 13.95mL,
41.9mmol) solution in water, and gained mixture is heated to 80 DEG C and continues 7 hours.LC-MS is shown complete conversion.It will
Reaction is cooled to 10 DEG C of <, is diluted with 30mL methyl tertiary butyl ether(MTBE), and is acidified with the aqueous HCl of 6M (10mL).Use other first
Base tertbutyl ether (20mL) extracts desired product from water layer.Combined organic extract is washed with salt water (20mL),
It is dried over sodium sulfate, filters, be then concentrated to provide title compound (741mg).1HNMR (501MHz, chloroform-d) δ ppm
2.84 (tt, J=12.8,3.4Hz, 1H), 1.85 (dd, J=13.4,3.4Hz, 2H), 1.53-1.40 (m, 2H), 1.27 (s,
6H), 1.24 (s, 6H)；MS(ESI+)m/z 187.0(M+H)+。
Example 54C
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- benzene
Base -1- (2,2,6,6- tetramethyl tetrahydro -2H- pyrans -4- carbonyl) pyrrolidines -2- formic acid esters
Example 54B (80mg, 0.430mmol) is dissolved in 2mL methylene chloride, addition oxalyl chloride (113 μ l,
1.289mmol), then n,N-Dimethylformamide is dripped in addition 1.Acquired solution is stirred at ambient temperature 2 hours, it is then dense
Contracting, and be re-dissolved in 0.5mL methylene chloride, to provide the solution of 2,2,6,6- tetramethyl tetrahydro -2H- pyrans -4- phosgenes.?
At 0 DEG C, by freshly prepd 2,2,6,6- tetramethyl tetrahydro -2H- pyrans -4- phosgenes (32.9mg, 0.161mmol) in 0.5mL
Solution in methylene chloride is added dropwise to example 34D (75mg, 0.161mmol) and triethylamine (44.8 μ l, 0.321mmol) in 1mL
In agitating solution in methylene chloride.After five minutes, show that reaction is completed by LC-MS.Reaction is sudden with the aqueous HCl of 1M (5mL)
It goes out, these layers is separated, and organic layer is concentrated in a vacuum, and residue is used into 0: 100 to 20: 80 ethyl acetate: heptan
Alkane is purified via flash chromatography, to provide the title compound of 89mg.1HNMR (4 ((MHz, dimethyl sulfoxide-d6)δ
Ppm 7.65 (s, 2H), 7.34 (t, J=7.5Hz, 2H), 7.25 (t, J=7.4Hz, 1H), 7.11 (dd, J=8.5,2.6Hz,
1H), 6.91 (d, J=2.6Hz, 1H), 6.72 (d, J=8.5Hz, 1H), 5.22 (d, J=6.8Hz, 1H), 4.55 (d, J=
2.9Hz, 1H), 4.11 (q, J=7.0Hz, 2H), 3.52 (s, 3H), 3.49 (d, J=13.6Hz, 1H), 3.32 (d, J=
13.6Hz, 1H), 2.65 (d, J=12.5Hz, 1H), 2.33 (s, 1H), 1.46 (d, J=13.0Hz, 1H), 1.30-1.22 (m,
4H), 1.20 (s, 9H), 1.19 (t, J=6.5Hz, 3H), 1.05 (s, 6H), 1.01 (br s, 3H), 1.00 (s, 9H), 0.95
(br s, 3H)；MS(ESI+)m/z 635.5(M+H)+。
Example 54D
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- phenyl -1-
(2,2,6,6- tetramethyl tetrahydro -2H- pyrans -4- carbonyl) pyrrolidines -2- formic acid
Example 54C (89mg, 0.140mmol) is dissolved in methanol (0.5mL), tetrahydrofuran (1.0mL) and water (1.000mL)
Mixture in.After adding lithium hydroxide monohydrate (58.8mg, 1.402mmol), reaction is heated to 40 DEG C and continues 16 hours,
Its completion is shown by LC-MS at this time.Mixture is cooled to environment temperature, and is acidified to pH=3 with the aqueous HCl of 1M.It will mix
It closes object to be extracted with methylene chloride (3x10mL), and combined extract is dried over sodium sulfate, filter and be concentrated to provide 55mg
Title compound.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.57 (s, 2H), 7.35 (t, J=7.5Hz, 2H),
7.26 (t, J=7.4Hz, 1H), 7.14 (dd, J=8.5,2.5Hz, 1H), 6.97 (s, 1H), 6.73 (d, J=8.5Hz, 1H),
5.22 (d, J=6.7Hz, 1H), 4.52 (d, J=2.3Hz, 1H), 3.58 (d, J=10.4Hz, 1H), 3.54 (dd, J=6.6,
1.8Hz, 1H), 3.50 (s, 3H), 3.38 (d, J=13.7Hz, 1H), 2.70 (br s, 1H), 2.37 (br s, 1H), 1.45 (d,
J=13.1Hz, 1H), 1.28 (s, 3H), 1.27-1.20 (m, 3H), 1.20 (s, 9H), 1.04 (s, 6H), 0.98 (s, 12H；3H
With the overlapping singlets of 9H)；MS(ESI+)m/z 607.3(M+H)+。
Example 55
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(5- tert-butyl -2- methoxypyridine -3- base) amino] -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid
By (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2-
Formic acid esters (example 7B, 56mg, 0.140mmol) and 3- bromo- 5- (tert-butyl) -2- methoxypyridine (68.3mg, 0.280mmol)
The solution through nitrogen jet be added to 2,2 '-bis- (diphenylphosphino) -1,1 '-dinaphthyl (9.58mg, 0.015mmol), three (two
BENZYLIDENE ACETONE) two palladiums (0) (6.40mg, 6.99 μm of ol) and cesium carbonate (137mg, 0.419mmol) be in toluene (0.3mL)
In suspension through nitrogen jet.Reaction is heated 16 hours at 110 DEG C in aluminium block.Rough material is concentrated and is loaded into
It on 12g silicagel column, and is eluted 40 minutes with 0-30% ethyl acetate/heptane, to provide (2S, 3S, 4S, 5S)-ethyl 3- (tertiary fourth
Base) -4- ((5- (tert-butyl) -2- methoxypyridine -3- base) amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid
Ester (16mg, 0.028mmol, 20.30% yield).MS(APCI+)m/z 610(M+H)+.Material is absorbed in methanol (1mL)
In, and the 1M solution of lithium hydroxide (0.284mL, 0.284mmol) in water is added into acquired solution.It will react at 45 DEG C
Warm 4 hours.Solvent is removed under nitrogen flowing, and the reaction aqueous HCl of 1N is neutralized.Rough material is absorbed in methylene chloride
In, and purified using 12g silicagel column ethyl acetate/ethyl alcohol/heptane solvent system, then reuse reversed-phase HPLC acetonitrile/
Water/trifluoroacetic acid method purifying, to provide (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxyl group pyrrole
Pyridine -3- base) amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid (4.8mg, 8.96 μm of ol, 31.6% yield).1HNMR (4 ((MHz, 120 DEG C, dimethyl sulfoxide-d6) δ ppm 7.49 (d, J=7.5Hz, 2H), 7.21 (d, J=2.1Hz, 1H),
7.17-7.03 (m, 3H), 6.77 (d, J=2.2Hz, 1H), 5.32 (d, J=7.2Hz, 1H), 4.44 (d, J=4.1Hz, 1H),
4.32 (s, 1H), 3.62 (s, 3H), 2.25 (t, J=3.9Hz, 1H), 2.18 (s, 1H), 1.72-1.59 (m, 3H), 1.44 (dd,
J=14.8,6.2Hz, 4H), 1.33-1.23 (m, 1H), 1.23 (s, 9H), 1.21-1.12 (m, 1H), 1.04 (s, 9H), 1.05-
0.93 (m, 1H)；MS(APCI+)m/z 536(M+H)+。
Example 56
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- hydroxyl -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 56A
Two rings [1.1.1] pentane -1- base methanol
At 0 DEG C, Xiang Erhuan [1.1.1] pentane -1- formic acid (4.0g, 35.7mmol) is molten in tetrahydrofuran (89mL)
Lithium aluminium hydride reduction (1.801g, 47.4mmol) is added batch-wise in liquid, which is acutely bubbled.Reaction is warmed to 24 DEG C and stirs 16
Hour.It will react cooling in ice bath, 4g sal glauberi is added batch-wise, is stirred to react 1 hour.Add 15%NaOH aqueous solution
(2mL).It stirs the mixture for 0.5 hour, adds 2mL water, and remove ice bath.It stirs the mixture for 2 hours, and anhydrous with 40g
Sodium sulphate is dry.Suspension is filtered and washs filtrate with ether.Solvent is removed in a vacuum, to provide two thick rings
[1.1.1] pentane -1- base methanol (3.2g, 32.6mmol, 91% yield).1HNMR (501MHz, chloroform-d) δ ppm 3.56 (s,
2H), 2.57 (s, 1H), 1.77 (s, 6H).
Example 56B
Two rings [1.1.1] pentane -1- formaldehyde
Example 56A (3.2g, 32.6mmol) is dissolved in 5mL methylene chloride.It is filled in individual 250-mL round-bottomed flask
Enter the oxalyl chloride (4.57mL, 52.2mmol) in 55mL methylene chloride, and flask is cooled to <-in acetone-dry ice bath
70℃.Through 20 minutes dropwise addition dimethyl sulfoxides (7.40mL, 104mmol), kept for < -60 DEG C of temperature.After the completion of addition, by gained
Solution stirs 15 minutes at the same temperature, after through 30 minutes addition two rings [1.1.1] pentane -1- base methanol (3.2g,
32.6mmol) the solution in methylene chloride (5mL) is kept for < -65 DEG C of temperature.After the completion of addition, by reaction mixture same
1 hour (allow to warm and be no more than -60 DEG C) is stirred at a temperature of one, at this time the three pure second through addition in 10 minutes at -78 DEG C
Amine (22.72mL, 163mmol).Generate very thick slurries.Flask is taken out from ice bath.After reaching environment temperature, it will react
The aqueous HCl quenching of 1M that mixture passes through addition 200mL.These layers are separated, and by organic layer with the aqueous HCl of 1M (30mL) and
Salt water washes twice, and is then dried over sodium sulfate, and filters and (the rotary evaporation bath at 10 DEG C) is concentrated in a vacuum, to provide
Two rings [1.1.1] pentane -1- formaldehyde (2.6g, 27.0mmol, 83% yield).1HNMR (501MHz, chloroform-d) δ ppm 9.52
(d, J=0.7Hz, 1H), 2.57 (d, J=0.8Hz, 1H), 2.11 (s, 6H).
Example 56C
1- (two rings [1.1.1] pentane -1- base) -2- nitroethyl alcohol
Example 56B (2.6g, 27.0mmol) and nitromethane (2.188mL, 40.6mmol) are dissolved in tetrahydrofuran
In (10mL) and the tert-butyl alcohol (3mL).After being cooled to 5 DEG C of < in ice bath, it is molten that potassium tert-butoxide (5.41mL, 5.41mmol) is added dropwise
Liquid.After 1 hour, ice bath is removed, and stir the mixture for 30 minutes.Mixture is poured into 40mL water and with the ether of 3x30mL
Extraction.Combined extract is washed with brine, is dried over sodium sulfate, filters, is then concentrated to provide thick residue.By thick object
Material is eluted 20 minutes on 40g silicagel column with 0-60% ethyl acetate/heptane, via flash column chromatography to provide
Desired product 1- (two rings [1.1.1] pentane -1- base) -2- nitroethyl alcohol (2.22g, 14.13mmol, 52.2% yield).1HNMR (500MHz, chloroform-d) δ ppm 4.49-4.38 (m, 1H), 4.36-4.27 (m, 2H), 2.61 (s, 1H), 2.32-2.29
(m, 1H), 1.85-1.78 (m, 6H)；MS(DCI+)m/z 175(M+NH4+)。
Example 56D
(E) -1- (2- nitroethenyl group) two rings [1.1.1] pentane
Example 56C (2.22g, 14.13mmol) is dissolved in 18.8mL anhydrous methylene chloride and solution is cooled to -78
℃.It adds triethylamine (4.92mL, 35.3mmol), mesyl chloride (1.321mL, 16.95mmol) then is added dropwise.Reaction is mixed
Object stirs 1 hour at the same temperature, removes and stirs 1 hour from ice bath.By mixture with saturation aqueous sodium bicarbonate and
Salt water washing, is then dried over sodium sulfate, and filtering is concentrated in a vacuum.By thick residue via flash column chromatography,
It is eluted 20 minutes on 24g silicagel column with 0-40% ethyl acetate/heptane, to provide desired product (E) -1- (2- nitro second
Alkenyl) two rings [1.1.1] pentane (1.63g, 11.71mmol, 83% yield).1HNMR (501MHz, chloroform-d) δ ppm 7.20
(d, J=13.4Hz, 1H), 6.88 (d, J=13.4Hz, 1H), 2.62 (s, 1H), 2.04 (s, 6H).
Example 56E
(2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -4- nitro -5- Phenylpyrrolidine -2- first
Acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.065g, 0.086mmol) and copper trifluoromethanesulfcomposite
(II) (0.017g, 0.034mmol) is dissolved in the tetrahydrofuran (9.5mL) for spraying 1 hour with nitrogen stream.Gained is mixed
Object stirs 1 hour (continuing nitrogen jet) at ambient temperature, and adds (E)-tert-butyl 2- (benzylideneamino) acetic acid esters
The solution of (1.040g, 4.74mmol) in 1mL tetrahydrofuran, and acquired solution is cooled to 5 DEG C of < in ice-water bath.It is added dropwise
2- methyl propyl- 2- potassium alcoholate (0.177mL, 0.177mmol) in tetrahydrofuran, then through 3 minutes addition example 56D (0.6g,
4.31mmol), temperature is kept to be lower than 7 DEG C.Reaction mixture is stirred 45 minutes at 0 DEG C.Mixture 6mL is saturated aqueous chlorine
Change ammonium and the quenching of 20mL diethyl ether, and is warmed to environment temperature.Ether layer is separated, is washed twice with saturated ammonium chloride, is then used
Salt water washing, is filtered by silicagel pad, and is concentrated, to provide thick residue, by its with normal heptane (50mL) dilute and stand with
Precipitating 2 hours.Mixture is filtered and is precipitated in the hot heptane of 50mL, to provide (2S, 3R, 4S, 5S)-tert-butyl 3- (two rings
[1.1.1] pentane -1- base) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (0.73g, 2.037mmol, 47.2% yield).1HNMR (400MHz, chloroform-d) δ ppm 7.44-7.30 (m, 5H), 5.01 (dd, J=5.7,2.0Hz, 1H), 4.47 (d, J=
5.5Hz, 1H), 3.74 (d, J=6.0Hz, 1H), 3.40 (bs, 1H), 3.02-2.92 (m, 1H), 2.69 (s, 1H), 1.96-
1.79 (m, 6H), 1.57 (s, 9H)；MS(ESI+)m/z 359(M+H)+。
Example 56F
(2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- nitro -5-
Phenylpyrrolidine -2- formic acid esters
At 25 DEG C, by example 56E (0.5g, 1.395mmol) and triethylamine (0.389mL, 2.79mmol) in dichloromethane
Solution in alkane (6.34mL) is handled dropwise with cyclohexanecarbonyl chloride (0.233mL, 1.744mmol).It is small to stir the mixture for 2
When, with the aqueous NaHCO of saturation3(5mL) and 1N NH4The washing of OH (1mL) aqueous solution, and be concentrated.Mixture is ground with 10mL heptane
It grinds and stands 0.5 hour at ambient temperature, and collect raw sediment (1.5g).Sediment is dissolved in 3mL methylene chloride simultaneously
Be loaded on 12g column, with gradient elution 20 minutes of 0-70% ethyl acetate/heptane, with provide desired product (2S, 3R,
4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- nitro -5- Phenylpyrrolidine -2- first
Acid esters (0.52g, 1.110mmol, 80% yield).1HNMR (501MHz, chloroform-d) δ ppm 7.76-7.64 (m, 2H), 7.45-
7.32 (m, 3H), 5.44 (d, J=8.9Hz, 1H), 5.09 (dd, J=11.1,8.9Hz, 1H), 4.12 (d, J=10.1Hz,
1H), 3.33 (t, J=10.6Hz, 1H), 2.55 (s, 1H), 2.11-1.98 (m, 1H), 1.85 (dd, J=9.6,2.0Hz, 3H),
1.77 (dd, J=9.6,2.0Hz, 3H), 1.72 (d, J=15.0Hz, 1H), 1.65 (s, 1H), 1.59 (s, 9H), 1.56-1.42
(m, 3H), 1.33-1.20 (m, 1H), 1.18-1.04 (m, 3H), 0.70-0.59 (m, 1H)；MS(ESI-)m/z 467(M-H)-.
Example 56G
(2S, 3S, 4S, 5S)-tert-butyl 4- amino -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid esters
In 50mL pressure bottle, to being added in the solution of example 56F (0.52g, 1.110mmol) and tetrahydrofuran (20mL)
RaNi:2800 aqueous slurry (3g, 23.00mmol).It will react in 50psi and stirred at ambient temperature 16 hours.Reaction is filtered,
And solvent is removed in a vacuum and is loaded on 12g column, with gradient elution 20 minutes of 0-9% ethanol/methylene, to give
(2S, 3S, 4S, 5S)-tert-butyl 4- amino -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -5- phenyl pyrazoline out
Cough up alkane -2- formic acid esters (0.432g, 0.985mmol, 89% yield).1HNMR (501MHz, chloroform-d) δ ppm 7.76-7.69
(m, 2H), 7.43 (td, J=7.4,6.8,0.9Hz, 2H), 7.37-7.31 (m, 1H), 4.95 (d, J=8.2Hz, 1H), 4.03
(d, J=9.7Hz, 1H), 3.80-3.74 (m, 1H), 3.47 (dd, J=10.3,8.1Hz, 1H), 2.56 (s, 1H), 2.16-
2.06 (m, 2H), 1.92-1.82 (m, 6H), 1.72 (t, J=12.5Hz, 2H), 1.60 (s, 1H), 1.57 (s, 9H), 1.46 (m,
3H), 1.34-1.22 (m, 1H), 1.12 (tt, J=12.4,6.3Hz, 3H), 0.72-0.59 (m, 1H)；MS(ESI+)m/z 439
(M+H)+。
Example 56H
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- hydroxyl -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
To 2- methoxyl group -5- (trifluoromethyl) benzaldehyde (30.7mg, 0.150mmol), example 56G (60mg,
0.137mmol) and zinc chloride (II) (18.64mg, 0.137mmol) be in methanol sodium acetate/acetate buffer (pH=4,
Sodium cyanoborohydride (12.89mg, 0.205mmol) is added in solution in 1mL), and it is small to react stirring 2 at ambient temperature
When.Solvent is removed, and gained residue is subjected to chromatography using 12g silicagel column, with the gradient of 0-60% ethyl acetate/heptane
Elution 20 minutes, to provide rough material (84mg, 0.134mmol, 98% yield).Rough material is dissolved in 2,2,2- trifluoroacetic acids
In (0.5mL, 6.49mmol), and stir 3 hours.Solvent is removed, and rough material is passed through into reverse phase using trifluoroacetic acid method
It is purified, to provide (2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ((2- first
Oxygroup -5- (trifluoromethyl) benzyl) amino) -5- Phenylpyrrolidine -2- methanoic acid trifluoro acetic acid (42mg, 0.061mmol, 44.8%
Yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.62-7.45 (m, 3H), 7.39-7.18 (m, 4H), 7.06 (d, J
=8.7Hz, 1H), 5.15 (d, J=7.4Hz, 1H), 4.12 (s, 1H), 3.73 (s, 3H), 3.61 (d, J=2.7Hz, 2H),
3.32 (t, J=7.3Hz, 1H), 2.50 (s, 1H), 2.44 (s, 1H), 2.31-2.12 (m, 1H), 1.76-1.69 (m, 6H),
1.67 (s, 1H), 1.49 (m, 2H), 1.27 (q, J=12.1Hz, 1H), 1.10 (m, 4H), 0.77 (bs, 1H)；MS(ESI+)m/z
571(M+H)+。
Example 57
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -
5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
To 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (30.9mg, 0.150mmol), example 56G (60mg, 0.137mmol)
It is with zinc chloride (II) (18.64mg, 0.137mmol) molten in sodium acetate/acetate buffer (pH=4,1mL) in methanol
Sodium cyanoborohydride (12.89mg, 0.205mmol) is added in liquid, and reaction is stirred 2 hours at ambient temperature.By solvent
Removal, and gained residue is subjected to chromatography using 12g silicagel column, divided with the gradient elution 20 of 0-60% ethyl acetate/heptane
Clock, to provide solid (80mg, 0.127mmol, 93%).Solid is dissolved in 2,2,2- trifluoroacetic acids (0.5mL, 6.49mmol)
In, and stir 3 hours at ambient temperature.Solvent is removed, and rough material is carried out using trifluoroacetic acid method by reverse phase
Purifying, to provide (2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- (((2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) -5- Phenylpyrrolidine -2- methanoic acid trifluoro acetate (45mg,
0.066mmol, 48.0% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.34 (d, J=2.1Hz, 1H), 7.67
(d, J=2.4Hz, 1H), 7.57 (s, 2H), 7.37-7.15 (m, 3H), 5.15 (d, J=7.4Hz, 1H), 4.10 (s, 1H),
3.86 (s, 3H), 3.57 (s, 2H), 3.29 (t, J=7.8Hz, 1H), 2.44 (s, 1H), 2.39 (bs, 1H), 2.21 (bs, 1H),
1.78-1.68 (m, 6H), 1.66 (m, 2H), 1.49 (m, 2H), 1.35-1.20 (m, 1H), 1.09 (m, 4H), 0.73 (bs, 1H)；
MS(ESI+)m/z 572.0(M+H)+。
Example 58
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl)-N- (mesyl) -5- Phenylpyrrolidine -2- formamide
Example 58A
Racemic-(2R, 3S, 4R, 5R) -3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- carboxylic acid hydrochloride
By racemic-(2R, 3S, 4R, 5R)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (core
2,2.0g, 6.24mmol) solution in 38% concentrated hydrochloric acid (12mL, 20.84mmol) and Isosorbide-5-Nitrae-dioxanes (4mL) is anti-in microwave
Answer device (Initiator it is irradiated 1 hour at 100 DEG C in).Sediment is collected by filtration and uses ethyl acetate
(5mL) washing, to provide the title compound (2.04g, 5.77mmol, 92% yield) for being in hydrochloride.LC/MS(ESI+)m/z
293.1(M+H)+。
Example 58B
Racemic-(2R, 3S, 4R, 5R) -3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- Phenylpyrrolidine -2-
Formic acid
At 0 DEG C, to example 58A (8.0g, 24.33mmol) and triethylamine (6.78mL, 48.7mmol) in methylene chloride
Cyclohexanecarbonyl chloride (2.497g, 17.03mmol) is added in solution in (50mL).Mixture is stirred 2 hours at 0 DEG C,
Then it is diluted with methylene chloride (100mL), with the aqueous NaHCO of saturation3(25mL) and salt water (25mL) washing, through MgSO4It is dry, mistake
It filters and is concentrated to provide title compound (9.5g, 22.19mmol, 91% yield).LC/MS(ESI+)m/z 403.2(M+H)+。
Example 58C
Racemic-(2R, 3S, 4R, 5R) -3- (tert-butyl)-l- (cyclohexane carbo)-N- (methyl sulphonyl) -4- nitro -
5- Phenylpyrrolidine -2- formamide
By example 58B (8.00g, 19.88mmol) and 1,1 '-carbonyl dimidazoles (9.67g, 59.6mmol) are in 1,2- dichloro
Solution in ethane (100mL) stirs 5 minutes at 42 DEG C.Into mixture add Methanesulfonamide (9.45g, 99mmol) and
1,8- diazabicylo [5.4.0], 11 carbon -7- alkene (DBU, 8.99mL, 59.6mmol) (is used DBU before the usePoint
Son sieve drying).Mixture is stirred 2 hours at 42 DEG C, is then diluted with ethyl acetate (200mL), with 1N HCL aqueous solution
(30mL) and salt water (30mL) washing, through Na2SO4Be dried, filtered and concentrated with provide title compound (8.8g, 12.48mmol,
62.8% yield).LC/MS(ESI+)m/z 480.2(M+H)+。
Example 58D
Racemic-(2R, 3R, 4R, 5R) -4- amino -3- (tert-butyl) -1- (cyclohexane carbo)-N- (methyl sulphonyl) -
5- Phenylpyrrolidine -2- formamide
To example 58C (5.00g, 10.43mmol) in 38% concentrated hydrochloric acid (10mL, 10.43mmol) and ethyl alcohol (50mL)
Solution in add zinc powder (13.63g, 209mmol).Mixture is stirred 2 hours at 60 DEG C.Solid is filtered and uses acetic acid
Ethyl ester (5mL) washing, to provide crude product, it is further passed through Combi- flash column chromatography purified (mobile phase:
H2O(5mmol NH4HCO3)(A)/CH3OH (B)), to provide title compound (2R, 3R, 4R, 5R) -4- amino -3- (tertiary fourth
Base) -1- (cyclohexane carbo)-N- (methyl sulphonyl) -5- Phenylpyrrolidine -2- formamide (845mg, 1.748mmol, 17%
Yield).1H NMR (400MHz, CDCl3) δ ppm 7.60 (d, J=8Hz, 2H), 7.39 (t, J=8Hz, 2H), 7.31 (t, J=
8Hz, 1H), 4.71 (s, 1H), 4.55 (d, J=12Hz, 1H), 3.64 (d, J=4Hz, 1H), 3.29 (s, 3H), 2.50 (dd, J
=4Hz, 8Hz, 1H), 2.05-2.08 (m, 1H), 1.73-1.82 (m, 2H), 1.09-1.52 (m, 7H), 1.09 (s, 9H),
0.73-0.74 (m, 1H)；LC/MS(ESI+)m/z 450.3(M+H)+。
Example 58E
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl)-N- (mesyl) -5- Phenylpyrrolidine -2- formamide
By 5- (tert-butyl)-Benzaldehyde,2-methoxy (61.6mg, 0.320mmol), racemic-(2R, 3R, 4R, 5R) -4-
Amino -3- (tert-butyl) -1- (cyclohexane carbo)-N- (methyl sulphonyl) -5- Phenylpyrrolidine -2- formamide (120mg,
0.267mmol) and zinc chloride (II) (7.27mg, 0.053mmol) be in methanol sodium acetate/acetate buffer (pH=4,
Mixture in 2mL) stirs 10 minutes at ambient temperature, to provide colourless solution.Addition sodium cyanoborohydride (25.2mg,
0.400mmol), it stirs the mixture for 1 hour, and adds methylene chloride (10mL).Organic layer is washed with brine, through MgSO4
It dries, filters, and is concentrated.Residue is purified on 12g silicagel column via chromatography, with methanol in methylene chloride with
It is separated [instrument: Aurora-2, column: Whelk- via chiral SFC to obtain racemic product by the gradient elution of 0-20%
O1 (S, S), 5-50% methanol: CO2, 10 minutes@3mL/ minutes, 150 bars].Elution the first compound be (2R, 3R, 4R,
5R) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (cyclohexane carbo)-N- (sulfonyloxy methyl
Base) -5- Phenylpyrrolidine -2- formamide (45mg, 26.9% yield).1HNMR (4 ((MHz, dimethyl sulfoxide-d6)δppm
11.5 (s, 1H), 7.63-7.52 (m, 2H), 7.36 (d, J=2.6Hz, 1H), 7.35-7.27 (m, 2H), 7.24 (d, J=
2.4Hz, 1H), 7.22 (d, J=2.6Hz, 1H), 6.89 (d, J=8.6Hz, 1H), 4.89 (s, 1H), 4.41 (d, J=
11.0Hz, 1H), 3.97 (d, J=13.5Hz, 1H), 3.84 (d, J=13.6Hz, 1H), 3.77 (s, 3H), 3.17 (s, 4H),
2.21 (dd, J=11.0,4.7Hz, 1H), 2.02 (s, 1H), 1.82 (s, 1H), 1.66 (d, J=10.1Hz, 2H), 1.48 (d, J
=10.7Hz, 2H), 1.26 (s, 9H), 1.20 (s, 2H), 1.11 (d, J=4.9Hz, 2H), 0.95 (s, 9H), 0.73 (s, 1H)；
MS(ESI+)m/z 626.1(M+H)+.The second compound of elution is title compound (2S, 3S, 4S, 5S) -3- (tert-butyl) -
4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (cyclohexane carbo)-N- (methyl sulphonyl) -5- Phenylpyrrolidine -
2- formamide (58.0mg, 34.7% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 11.49 (s, 1H), 7.62-
7.53 (m, 2H), 7.36 (d, J=2.6Hz, 1H), 7.31 (t, J=7.5Hz, 2H), 7.23 (dd, J=8.6,2.5Hz, 2H),
4.89 (s, 1H), 4.41 (d, J=11.0Hz, 1H), 3.97 (d, J=13.5Hz, 1H), 3.4 (d, J=13.5Hz, 1H), 3.77
(s, 3H), 3.16 (s, 4H), 2.21 (dd, J=11.0,4.7Hz, 1H), 2.02 (s, 1H), 1.82 (s, 1H), 1.66 (d, J=
10.1Hz, 2H), 1.48 (d, J=10.8Hz, 2H), 1.26 (s, 9H), 1.18-1.10 (m, 4H), 0.94 (s, 9H), 0.73 (s,
1H)；MS(ESI+)m/z 626.1(M+H)+。
Example 59
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 59A
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- (difluoro-methoxy) phenyl) -1- ((S)-four
Hydrogen -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Replace example 36B with example 45A, title compound is prepared according to program described in example 36C.
Example 59B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Fluorine methoxyl group) phenyl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Replace example 45C with example 59A, title compound is prepared according to program described in example 45D.1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.87 (s, 1H), 7.31 (t, J=7.9Hz, 1H), 7.19 (t, J=7.6Hz,
1H), 7.16-7.10 (m, 2H), 6.97 (s, 1H), 6.93 (d, J=2.5Hz, 1H), 6.72 (d, J=8.5Hz, 1H), 5.6 (s,
1H), 4.59 (d, J=1.7Hz, 1H), 3.74 (d, J=11.4Hz, 2H), 3.55 (d, J=13.6Hz, 1H), 3.51 (s, 3H),
3.46 (d, J=6.8Hz, 1H), 3.26 (d, J=13.8Hz, 2H), 2.37-2.31 (m, 1H), 1.89 (s, 1H), 1.74-1.30
(m, 6H), 1.18 (s, 9H), 0.97 (s, 9H)；MS(ESI+)m/z 617.2(M+H)+。
Example 60
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 60A
(2S, 3R, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4-
Nitro-pyrrole alkane -1,2- dicarboxylic acid esters
Core 11 (18.2g, 50mmol) is dissolved in 100mL tetrahydrofuran, and add di-tert-butyl dicarbonate (16.37g,
75mmol).Reaction mixture is heated to 50 DEG C and continues 3 hours, conversion completely occurs at this time, as by shown in LC-MS.It will burn
Bottle is cooled to environment temperature and adds imidazoles (3.4g, 50mmol).Reaction mixture stirs to 5 minutes at ambient temperature, so
It is diluted afterwards with methyl tertiary butyl ether(MTBE) (100mL).By suspension with the aqueous HCl of 1M (3x50mL) then with saturation aqueous sodium bicarbonate
(50mL) and salt water (50mL) are washed and are dried over sodium sulfate, and are filtered and are concentrated in a vacuum to provide the title compound of 23g.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.18 (dd, J=4.8,1.7Hz, 1H), 8.06 (dd, J=7.7,1.8Hz,
1H), 6.97 (ddd, J=7.7,4.7,0.9Hz, 1H), 5.63 (d, J=8.3Hz, 1H), 5.48 (ddd, J=8.3,2.5,
1.0Hz, 1H), 4.50 (d, J=3.2Hz, 1H), 4.24 (q, J=7.1Hz, 2H), 2.92 (t, J=2.9Hz, 1H), 2.75 (s,
6H), 1.95 (s, 1H), 1.28 (td, J=7.1,0.9Hz, 3H), 1.20 (s, 9H), 1.03 (s, 9H)；MS(ESI+)m/
465.3(M+H)+。
Example 60B
(2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 4- amino -3- (tert-butyl) -5- (2- (dimethylamino) pyridine -
3- yl) pyrrolidines -1,2- dicarboxylic acid esters
Example 60A (20.6g, 44.3mmol) and tetrahydrofuran (200mL) are added in 50mL Hast C reactor
'sIn 2800 aqueous slurry of nickel (81g, 621mmol), and mixture is stirred 22 hours at 60psi hydrogen and 60 DEG C,
And it is stirred 16 hours at 25 DEG C.Reaction mixture is filtered by sinter funnel, and filter cake is washed with 50mL tetrahydrofuran.
Filtrate is concentrated to provide title compound (18.9g) in a vacuum, it is used without other purifying.1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.32-8.00 (m, 2H), 6.97 (dd, J=7.5,4.8Hz, 1H), 5.19 (d, J
=6.7Hz, 1H), 4.27 (d, J=3.0Hz, 1H), 4.18 (qq, J=7.0,3.8Hz, 2H), 3.75 (dd, J=6.7,
2.2Hz, 1H), 2.75 (s, 6H), 2.01 (t, J=2.6Hz, 1H), 1.25 (t, J=7.1Hz, 3H), 1.15 (s, 9H), 1.00
(s, 9H)；MS(ESI+)m/z 435.1(M+H)+。
Example 60C
(2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4-
((2- methoxyl group -5- (1- methyl-cyclobutyl) benzyl) amino) pyrrolidines -1,2- dicarboxylic acid esters
By example 60B (130mg, 0.299mmol) and 2- methoxyl group -5- (1- methyl-cyclobutyl) benzaldehyde (intermediate 5,
73.3mg, 0.359mmol) it is dissolved in dichloroethanes (1496 μ L).Disposable addition sodium triacetoxy borohydride (89mg,
0.419mmol), and by reaction it stirs 0.5 hour at ambient temperature, its completion is shown by LC-MS at this time.By solution with two
Chloromethanes (5mL) dilution, and add 1mL saturation aqueous sodium bicarbonate.It stirs the mixture for 10 minutes, then uses 3x5mL dichloro
Methane extraction, and combined organic extract is dried over sodium sulfate, filter and is concentrated in a vacuum.Material is dissolved in cyclopenta
In methyl ether (5mL).Add the HCl in cyclopentyl methyl ether (3M, 0.2mL, 0.6mmol).Solution is diluted with heptane (10mL),
And remove obtained solid material via filtering by sinter funnel, to provide title compound (197mg).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 8.28 (d, J=7.8Hz, 1H), 8.19 (d, J=5.1Hz, 1H), 7.08 (s,
1H), 7.00 (d, J=8.6Hz, 1H), 6.84 (s, 1H), 6.78 (d, J=8.1Hz, 1H), 5.28 (d, J=6.4Hz, 1H),
4.38 (d, J=1.7Hz, 1H), 4.17 (q, J=7.1Hz, 2H), 3.74-3.58 (m, 4H), 3.55 (s, 3H), 2.76 (br s,
6H), 2.20 (m, 2H), 2.08-1.91 (m, 3H), 1.77-1.70 (m, 1H), 1.33 (s, 3H), 1.22 (t, J=7.1Hz,
3H), 1.16 (s, 9H), 1.02 (s, 9H)；MS(ESI+)m/z 623.1(M+H)+。
Example 60D
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- ((2- methoxy
Base -5- (1- methyl-cyclobutyl) benzyl) amino) pyrrolidines -2- formic acid esters
Example 60C (200mg, 0.303mmol) is dissolved in 2mL methylene chloride, and adds 0.5mL trifluoroacetic acid.In ring
At a temperature of border after 2 hours, reaction mixture is concentrated in a vacuum and is distributed in the aqueous NaOH of 1M and methylene chloride.It will be organic
Extract is dried over sodium sulfate, and is filtered and be concentrated to provide crude product (160mg), it is used without other purifying.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.13 (dd, J=4.6,1.9Hz, 1H), 7.98 (dd, J=7.6,2.0Hz,
1H), 6.99-6.85 (m, 2H), 6.85-6.65 (m, 2H), 4.42 (s, 1H), 4.13 (qt, J=7.1,3.5Hz, 2H), 3.59
(br s, 4H), 3.43-3.22 (m, 2H), 3.08 (br s, 1H), 2.82 (br s, 1H), 2.72 (s, 6H), 2.20 (ddd, J=
10.6,6.2,4.0Hz, 2H), 2.12 (dd, J=5.9,1.9Hz, 1H), 2.07-1.89 (m, 3H), 1.75 (tdd, J=9.2,
7.2,4.2Hz, 1H), 1.33 (s, 3H), 1.20 (t, J=7.1Hz, 3H), 0.96 (s, 9H)；MS(ESI+)m/z 523.2(M+
H)+。
Example 60E
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4- ((2- methoxy
Base -5- (1- methyl-cyclobutyl) benzyl) amino) -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Example 60D (160mg, 0.306mmol) is dissolved in 2mL methylene chloride, solution is cooling in ice bath, Zhi Houtian
Add triethylamine (0.171mL, 1.224mmol) and tetrahydro -2H- pyrans -2- phosgene (59.1mg, 0.398mmol) in dichloromethane
Solution in alkane (0.5mL).After five minutes, reaction mixture is diluted with methyl tertiary butyl ether(MTBE) (30mL), with the aqueous carbonic acid of saturation
Hydrogen sodium (15mL) stirs 15 minutes, is then extracted with methyl tertiary butyl ether(MTBE) (3x10mL).Combined extract is concentrated to provide
Thick residue, by it via purified by flash chromatography, in 40g silicagel column with 0: 100 to 60: 40 methyl tertiary butyl ether(MTBE)s: heptane is washed
It is 5 minutes de-, and with isocratic 60: 40 methyl tertiary butyl ether(MTBE): heptane elutes, to provide two kinds of diastereoisomer products.First
A eluting peak (57mg) is title compound.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.17 (s, 2H), 6.93 (dd,
J=8.4,2.5Hz, 2H), 6.83-6.62 (m, 2H), 5.56 (s, 1H), 4.67 (s, 1H), 4.21-4.01 (m, 3H), 3.75
(d, J=11.4Hz, 1H), 3.55 (br s, 2H), 3.48 (s, 3H), 3.24 (s, 2H), 2.69 (s, 6H), 2.19 (t, J=
9.3Hz, 2H), 2.10-1.88 (m, 3H), 1.80-1.60 (m, 2H), 1.43 (d, J=42.0Hz, 3H), 1.32 (s, 5H),
1.19 (t, J=7.0Hz, 4H), 1.01 (s, 9H)；MS(ESI+)m/z 635.6(M+H)+。
Example 60F
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 60E (54mg, 0.085mmol) is dissolved in 0.2mL tetrahydrofuran and water (0.200mL) and methanol
In (0.100mL) mixture.It adds lithium hydroxide monohydrate (17.85mg, 0.425mmol), and suspension is heated to 50 DEG C
Continue 1 hour, LC-MS shows to convert completely at this time.Bottle is cooled to environment temperature, is diluted with methylene chloride (20mL), and
PH 3-4 is acidified to the aqueous HCl of 1M.These layers are separated.Organic layer is dried over sodium sulfate, is filtered and in N2It flows down 50
DEG C concentration, to provide the title compound of 49mg.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.19 (dd, J=4.8,
1.6Hz, 2H), 7.05-6.92 (m, 2H), 6.83-6.72 (m, 2H), 5.57 (d, J=6.6Hz, 1H), 4.60 (s, 1H),
3.81-3.58 (m, 6H), 3.52 (s, 3H), 3.29 (d, J=13.7Hz, 1H), 2.71 (s, 6H), 2.66 (br s, 1H), 2.44
(s, 1H), 2.25-2.14 (m, 2H), 2.10-1.88 (m, 3H), 1.81-1.62 (m, 3H), 1.51-1.36 (m, 3H), 1.33
(s, 3H), 1.00 (s, 9H)；MS(ESI+)m/z 607.3(M+H)+。
Example 61
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 61A
(2S, 3R, 4S, 5S) -3- tert-butyl -5- (2- isopropyl-phenyl) -4- nitro-pyrrole alkane -1,2- dioctyl phthalate uncle 1-
Butyl ester 2- ethyl ester
To (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
(core 8,3.15g, 8.69mmol, 1.0 equivalent) adds di-tert-butyl dicarbonate in the solution in tetrahydrofuran (25mL)
(2.84g, 13mmol, 1.5 equivalent).Reaction mixture is stirred overnight at 55 DEG C, then with imidazoles (591mg,
8.69mmol, 1 equivalent) quenching, and diluted with ethyl acetate.By acquired solution 1N HCl solution, water and salt water washing.It will close
And organic layer it is dried over magnesium sulfate, filter simultaneously be concentrated in a vacuum.By title compound (4.2g, quantitative yield) without in addition
Purifying i.e. be used in next step.LC/MS(ESI+)m/z 463.4(M+H)+。
Example 61B
(2S, 3S, 4S, 5S) -4- amino -3- tert-butyl -5- (2- isopropyl-phenyl)-pyrrolidines -1,2- dioctyl phthalate uncle 1-
Butyl ester 2- ethyl ester
Zinc powder (12.2g, 187mmol, 21 equivalent) is added to example 61A (8.69mmol, 1 equivalent) at acetic acid (30mL)
In the solution in ethyl acetate (100mL).Gained mixture is stirred 1 hour at 60 DEG C.By reaction mixture in diatom
It filters on soil, is washed with ethyl acetate, concentration is then with saturation NaHCO3Aqueous solution quenching.Crude mixture ethyl acetate is dilute
Release and use water and salt water washing.By combined organic layer through MgSO4It dries, filters and is concentrated in a vacuum.By title compound
(4.5g, quantitative) is without other purifying i.e. in following step.LC/MS(ESI+)m/z 433.5(M+H)+。
Example 61C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- (2- isopropyl-benzene
Base)-pyrrolidines -1,2- dioctyl phthalate 1- tert-butyl ester 2- ethyl ester
By NaBH3CN (8mg, 0.12mmol, 1.2 equivalent) be added to example 61B (40mg, 0.09mmol, 1.0 equivalent) and
5- tert-butyl -2- Methoxy-benzaldehyde (19mg, 0.1mmol, 1.1 equivalent) is in acetic acid/sodium acetate/methanol buffer (2mL)
Solution in.Reaction mixture is stirred at room temperature 1 hour.Mixture is concentrated, and by residue methylene chloride and water it
Between distribute.Organic phase is concentrated to dryness, and residue is purified to (heptane/ethyl acetate 100/0 to 70/ on silica gel
30), to provide title compound (350mg, 57%).LC/MS(ESI+)m/z 609.6(M+H)+。
Example 61D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- (2- isopropyl-benzene
Base)-pyrrolidines -2- Ethyl formate
Trifluoroacetic acid (CAS# 76-05-1,350 μ L) is added to (2S, 3S, 4S, 5S) -3- tert-butyl -4- through protecting
(5- tert-butyl -2- Methoxy-benzylamino) -5- (2- isopropyl-phenyl)-pyrrolidines -1,2- dioctyl phthalate 1- tert-butyl ester 2- second
In the solution of ester (145mg, 0.25mmol, 1.0 equivalent) in methylene chloride.Reaction is stirred at room temperature overnight, and will be molten
Agent removes under vacuum.By residue in methylene chloride and NaHCO3It is distributed between saturated aqueous solution.Organic phase is concentrated to dryness,
And residue is purified into (methylene chloride/methanol 100/0 to 97/3) by flashchromatography on silica gel, to provide title compound
(90mg, 70%).LC/MS(ESI+)m/z 509.8(M+H)+。
Example 61E
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- (2- isopropyl-benzene
Base)-pyrrolidines -1,2- dioctyl phthalate 2- ethyl ester 1- isopropyl ester
At room temperature, to (2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5-
(2- isopropyl-phenyl)-pyrrolidines -2- Ethyl formate (45mg, 0.08mmol, 1.0 equivalent) and triethylamine (22 μ L,
0.16mmol, 2.0 equivalents) in the agitating solution in methylene chloride (2mL) add isopropyl chlorocarbonate (CAS# 108-23-6,
90 μ L, 0.09mmol, 1.1 equivalents).Reaction mixture is stirred 1 hour, is then washed with water and is concentrated to dryness organic phase.
By residue by purified by flash chromatography (heptane/ethyl acetate 100/0 to 85/15), with provide title compound (52mg,
100%)；LC/MS(ESI+)m/z 596.0(M+H)+.
Example 61F
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- (2- isopropyl-benzene
Base)-pyrrolidines -1,2- dioctyl phthalate 1- isopropyl ester
At room temperature, by (2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5-
(2- isopropyl-phenyl)-pyrrolidines -1,2- dicarboxylic acid ethyl ester 1- isopropyl ester (52mg, 0.08mmol, 1.0 equivalent) is in methanol
LiOH 1.0M (240 μ L, 0.24mmol, the 3.0 equivalent) processing of solution in water in (1mL), and by mixture at 45 DEG C
Lower stirring 96 hours.After completion of the reaction, the aqueous HCl of 2N is added, and solvent is removed under vacuum.Residue is passed through into silica gel
Chromatography purifies (methylene chloride/methanol 100/0 to 95/5).Product fraction is merged, and is concentrated to dryness to provide title compound
Object (33mg, 72%).LC/MS(ESI+)m/z 567.7(M+H)+。
Example 62
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(2S*)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 62A
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- (2- isopropyl-benzene
Base) -1- (ttetrahydro-pyran -2- carbonyl)-pyrrolidines -2- Ethyl formate
To ttetrahydro-pyran -2- formic acid (CAS# 51673-83-7,13mg, 0.10mmol, 1.3 equivalent) in methylene chloride
Ghosez ' s reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, CAS# 26189-59- are added in agitating solution in (1mL)
3,32 μ L, 0.24mmol, 3.0 equivalents).Reaction mixture is stirred 5 minutes at 0 DEG C, and is added in methylene chloride (1mL)
Example 61D (45mg, 0.08mmol, 1.0 equivalent) and diethylamine (56 μ L, 0.32mmol, 4.0 equivalent).By reaction mixture
It stirs 10 minutes and is stirred at room temperature 1.5 hours at 0 DEG C.Water is added, two phases were separated and is concentrated to dryness organic phase.It will
Residue is purified by silica gel chromatography (heptane/ethyl acetate 100/0 to 85/15), is in the mixed of diastereoisomer to provide
Close the title compound (54mg, 100%) of object.LC/MS(ESI+)m/z 621.6(M+H)+。
Example 62B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5- (2- isopropyl-benzene
Base) -1- ((S)-ttetrahydro-pyran -2- carbonyl)-pyrrolidines -2- formic acid
At room temperature, by (2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- Methoxy-benzylamino) -5-
(2- isopropyl-phenyl) -1- (ttetrahydro-pyran -2- carbonyl)-pyrrolidines -2- Ethyl formate (54mg, 0.08mmol, 1.0 equivalent)
LiOH1.0M (240 μ L, 0.24mmol, the 3.0 equivalent) processing of solution in methanol (2mL) in water, and by mixture
It is stirred 96 hours at 45 DEG C.After completion of the reaction, the aqueous HCl of 2N is added, and solvent is removed under vacuum.Residue is existed
(methylene chloride/methanol 100/0 to 95/5) is purified on silica gel.Product fraction is merged, and is concentrated to dryness to provide title
Examples of compounds 62B (8mg, 17%, the second diastereoisomer of elution).LC/MS(ESI+)m/z 593.8(M+H)+.Also
It obtains example 1-217 (9mg, 17%), the first diastereoisomer as elution.
Example 63
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [4- (3- chlorphenyl) oxane -4- base] methyl } amino) -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid
It is packed into stirring rod into 4mL bottle, sodium acetate/acetate buffer of the addition in 800 μ L in methanol into the bottle
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine-in liquid (pH=4)
2- formic acid esters (example 7B, 25mg, 0.063mmol).4- (3- chlorphenyl) tetrahydro -2H- pyrans -4- formaldehyde is added thereto
The solution of (13mg, 0.07mmol) in methanol (200 μ L) then adds sodium cyanoborohydride (5mg, 0.081mmol).It will be anti-
Mixture is answered to be stirred at room temperature overnight.It is after the completion of first step, rough material is dry, and tetrahydrofuran is added into residue
With 3: 2 mixtures of methanol and the 5M aqueous lithium of 300 μ L, and further it is stirred overnight at 45 DEG C.By residue
It is dissolved in dimethyl sulfoxide, and is purified by reversed-phase HPLC (trifluoroacetic acid method).Sample is existed by preparative HPLCC8(2)5μmIt is purified on AXIA column (30mm × 150mm).Use ACN (A) He Shui's
The gradient of 0.1% trifluoroacetic acid (B), flow velocity are 50mL/ minutes (0-0.5 minutes 5%A, 0.5-8.5 minutes linear gradient 5%-
100%A, 8.7-10.7 minutes 100%A, 10.7-11.0 minutes linear gradient 100%-5%A), to obtain desired chemical combination
Object.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.35 (s, 2H), 7.17 (t, J=5.9Hz, 2H), 7.15-7.06 (m,
3H), 6.93 (t, J=2.0Hz, 1H), 6.87 (dt, J=7.5,1.7Hz, 1H), 5.08 (d, J=7.0Hz, 1H), 4.41 (d, J
=2.6Hz, 1H), 3.56-3.41 (m, 2H), 3.37 (ddd, J=11.5,7.5,3.5Hz, 1H), 3.30-3.23 (m, 2H),
2.64 (d, J=12.0Hz, 1H), 2.26 (d, J=11.8Hz, 1H), 2.15 (s, 2H), 1.83-1.74 (m, 1H), 1.66-
1.37 (m, 7H), 1.18 (t, J=12.6Hz, 3H), 1.06 (d, J=19.8Hz, 2H), 0.93 (s, 9H)；MS(APCI)m/z
581.1(M+H)+。
Example 64
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 64A
2- ethyl 1- isopropyl (2S, 3S, 4S, 5S) -4- ((5- (two rings [1.1.1] pentane -1- base) -2- methoxybenzyl
Base) amino) -3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -1,2- dicarboxylic acid esters
By (2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -3- (tert-butyl) -5- (2- (dimethylamino) pyrrole
Pyridine -3- base) pyrrolidines -1,2- dicarboxylic acid esters (example 66B, 84.9mg, 0.202mmol) and example 51B (61.9mg,
It 0.284mmol) is dissolved in dichloroethanes (2mL).It adds sodium triacetoxy borohydride (69.0mg, 0.326mmol), and will be anti-
It should stir at ambient temperature 1 hour.By reaction with methylene chloride (25mL) dilute, and be saturated aqueous sodium bicarbonate (25mL)
Quenching, and stir 30 minutes.Organic layer is separated, and water layer is extracted with methylene chloride (25mL).Combined organic layer is passed through
Na2SO4It is dried, filtered and concentrated.Residue is dissolved in heptane, and HCl (3M in cyclopentyl methyl ether, 2mL) is added dropwise.By institute
Solid is obtained via filtering removal and drying, to provide the product (126.4mg, 97%) for being in HCl salt.1HNMR (4 ((MHz, diformazans
Base sulfoxide-d6, 120 DEG C) and δ ppm 8.26 (d, J=8.1Hz, 1H), 8.19 (d, J=5.0Hz, 1H), 7.10-7.03 (m, 1H),
6.97 (d, J=8.3Hz, 1H), 6.81 (s, 1H), 6.76 (d, J=8.1Hz, 1H), 5.33 (d, J=6.5Hz, 1H), 4.63
(p, J=6.2Hz, 1H), 4.40 (d, J=1.7Hz, 1H), 4.17 (q, J=7.1Hz, 2H), 3.68-3.52 (m, 5H), 3.30
(d, J=14.2Hz, 1H), 3.14 (s, 1H), 2.77 (t, J=2.4Hz, 6H), 2.45 (s, 1H), 1.95 (s, 6H), 1.22 (t,
J=7.1Hz, 3H), 1.05-0.98 (m, 12H), 0.86 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 607(M+H)+。
Example 64B
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 64A (126.4mg, 0.197mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 1.0mL,
1.0mmol) and reaction is heated to 50 DEG C and continues 16 hours.Reaction is acidified to pH=5 by the addition aqueous HCl of 1M (1mL),
Then it is concentrated.Residue is purified by silica gel chromatography (10% ethyl alcohol in ethyl acetate), to provide title compound
(58.2mg, 51%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.21-8.12 (m, 2H), 6.98-6.89
(m, 2H), 6.77 (d, J=2.2Hz, 1H), 6.71 (d, J=8.3Hz, 1H), 5.29 (d, J=6.4Hz, 1H), 4.60 (p, J=
6.2Hz, 1H), 4.33 (d, J=1.6Hz, 1H), 3.53 (d, J=13.8Hz, 1H), 3.46 (d, J=5.7Hz, 4H), 3.22
(d, J=13.8Hz, 1H), 2.62 (d, J=0.9Hz, 6H), 2.49 (s, 1H), 2.33 (d, J=1.6Hz, 1H), 1.94 (s,
6H), 1.04-0.96 (m, 12H), 0.81 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 579(M+H)+。
Example 65
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 65A
(2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl)
Amino) -5- Phenylpyrrolidine -1,2- dicarboxylic acid esters
By (2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 4- amino -3- (tert-butyl) -5- Phenylpyrrolidine -1,2- diformazan
Acid esters (example 34B, 1.3g, 3.33mmol) and 2- methoxyl group -4- (trifluoromethyl) benzaldehyde (0.680g, 3.33mmol) are dissolved in
In dichloroethanes (11.10mL).It adds sodium triacetoxy borohydride (0.882g, 4.16mmol), and reaction mixture is existed
Stirred at ambient temperature 15 minutes, show that reaction is completed by LC-MS at this time.Gained suspension will be used into methyl tertiary butyl ether(MTBE)
(30mL) dilution, and stirred 15 minutes with saturation aqueous sodium bicarbonate (20mL).These layers are separated, and by organic layer in vacuum
Middle concentration is to provide thick residue, and be loaded on 40g silicagel column and with 0: 100 to 15: 85 ethyl acetate: heptane elutes 20
Minute, to provide the title compound of 1.45g.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.59-7.40 (m, 2H),
7.35-7.14 (m, 3H), 7.13-7.01 (m, 3H), 4.96 (d, J=6.8Hz, 1H), 4.31 (d, J=2.7Hz, 1H), 4.12
(q, J=7.1Hz, 2H), 3.64 (s, 3H), 3.49-3.27 (m, 3H), 2.27 (t, J=2.5Hz, 1H), 1.20 (d, J=
7.1Hz, 3H), 1.18 (d, J=3.3Hz, 9H), 0.99 (s, 9H)；MS(ESI+)m/z 579.1(M+H)+。
Example 65B
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -5- benzene
Base pyrrolidines -2- formic acid esters
Example 65A (1.25g) is dissolved in the mixture of methylene chloride (10mL) and trifluoroacetic acid (5mL), and by solution
At ambient temperature stir 1 hour, then in a vacuum concentration and with 10mL methylene chloride azeotropic twice.Residue is dissolved in second
It washs in acetoacetic ester (20mL) and with the aqueous NaOH of 1M (3x10mL) and salt water (10mL), is dried over sodium sulfate later, filter, and
It is concentrated, to provide title compound (1.0g), it is used without other purifying in a vacuum.1HNMR (400MHz, chlorine
Imitative-d) δ ppm 7.39-7.31 (m, 4H), 7.30-7.24 (m, 1H), 7.13-7.01 (m, 2H), 6.90 (d, J=1.5Hz,
1H), 4.29-4.17 (m, 3H), 3.74 (d, J=5.7Hz, 1H), 3.63 (s, 3H), 3.42 (s, 1H), 3.32 (d, J=
14.4Hz, 1H), 3.12 (dd, J=4.7,1.3Hz, 1H), 2.15 (dd, J=5.8,1.3Hz, 1H), 1.76 (br s, 2H),
1.28 (t, J=7.2Hz, 3H), 1.00 (s, 9H)；MS(ESI+)m/z 479.5(M+H)+。
Example 65C
Ethyl (2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- (tert-butyl) -4- ((2- methoxyl group -
4- (trifluoromethyl) benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters
Two rings [3.1.0] hexane -6- formic acid (29.4mg, 0.233mmol) is dissolved in methylene chloride (1mL).Addition grass
Acyl chlorides (40 μ L, 0.457mmol) then adds n,N-Dimethylformamide (10 μ L).Reaction is stirred at room temperature 3 hours, this
When be concentrated, be re-dissolved in methylene chloride (1mL) and be concentrated again.Residue is absorbed in methylene chloride (2x1mL),
And it is added to (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoro in methylene chloride (1mL)
Methyl) benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters (example 65B) (54.7mg, 0.114mmol) and triethylamine (50 μ
L, 0.359mmol) in.Reaction is stirred 17 hours at ambient temperature.Reaction is concentrated, and thick residue is used into ammonium acetate
Method is purified by reverse phase, to provide title compound (64.9mg, 97%).1HNMR (400MHz, dimethyl sulfoxide-d6,
120 DEG C) δ ppm 7.58 (d, J=7.5Hz, 2H), 7.32 (t, J=7.5Hz, 2H), 7.28-7.22 (m, 1H), 7.11-7.02
(m, 3H), 5.24 (d, J=6.8Hz, 1H), 4.52 (d, J=2.7Hz, 1H), 4.10 (q, J=7.1Hz, 2H), 3.64 (s,
3H), 3.51-3.31 (m, 4H), 2.28 (d, J=2.7Hz, 1H), 1.69-1.53 (m, 3H), 1.49-1.30 (m, 3H), 1.18
(t, J=7.1Hz, 3H), 1.13 (s, 1H), 0.98 (s, 9H), 0.65 (s, 1H)；MS(ESI+)m/z 587(M+H)+。
Example 65D
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 65C (64.9mg, 0.111mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in trifluoroacetate
Title compound (52.5mg, 71%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.61-7.54 (m, 2H),
7.36 (t, J=7.6Hz, 2H), 7.32-7.25 (m, 1H), 7.20-7.07 (m, 3H), 5.32 (d, J=6.9Hz, 1H), 4.53
(d, J=2.2Hz, 1H), 3.71-3.67 (m, 4H), 3.64 (d, J=14.2Hz, 1H), 3.40 (d, J=14.2Hz, 1H),
2.44-2.37 (m, 2H), 1.81-1.03 (m, 7H), 1.00 (s, 9H), 0.79-0.60 (m, 1H)；MS(ESI+)m/z 559(M+
H)+。
Example 66
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 66A
(2S, 3R, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4-
Nitro-pyrrole alkane -1,2- dicarboxylic acid esters
It at room temperature, will be in CH2Cl2(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- (diformazan in (8.3mL)
Base amino) pyridin-3-yl) -4- nitro-pyrrole alkane -2- formic acid ester hydrochloride (core 11,1g, 2.494mmol) uses triethylamine
(1.1mL, 7.89mmol) processing, then at isopropyl chlorocarbonate (the 1M solution in toluene) (4.6mL, 4.60mmol)
Reason.Reaction is stirred at room temperature overnight.It will volatilize object to remove in a vacuum, and rough material be purified by silica gel chromatography, use
The elution of 5% to 80% ethyl acetate-heptane.It obtains title compound 0.548g (49% yield).1HNMR (501MHz, dimethyl
Sulfoxide-d6) δ ppm 8.20 (dd, J=4.8,1.9Hz, 1H), 8.05 (dd, J=7.7,1.9Hz, 1H), 7.03 (dd, J=
7.7,4.8Hz, 1H), 5.64 (m, 1H), 5.52 (dd, J=8.5,3.0Hz, 1H), 4.64 (m, 1H), 4.47 (m, 1H), 4.23
(qd, J=7.2,1.4Hz, 2H), 2.97 (m, 1H), 2.71 (s, 6H), 1.26 (t, J=7.1Hz, 3H), 1.14-0.85 (m,
6H), 0.98 (s, 9H)；MS(ESI+)m/z 451.1(M+H)+。
Example 66B
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -3- (tert-butyl) -5- (2- (dimethylamino) pyridine -
3- yl) pyrrolidines -1,2- dicarboxylic acid esters
It will be added in the example 66A (0.548g, 1.216mmol) in tetrahydrofuran (20mL) in 250mL SS pressure bottle
In weighing after through solvent washing2800 aqueous slurry of nickel (1.59g, 12.19mmol) uses hydrogen with argon cleaning 3 times
Gas flushing, and vibrated 17 hours at 60 DEG C under 50psi hydrogen.Then mixture is filtered by polypropylene screen, and will filter
Liquid is concentrated in a vacuum to provide title compound, 0.474g (93% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δ
Ppm 8.23-8.11 (m, 2H), 7.00 (dd, J=7.6,4.8Hz, 1H), 5.15 (d, J=6.5Hz, 1H), 4.50 (m, 1H),
4.24-4.10 (m, 3H), 3.73 (m, 1H), 2.72 (s, 6H), 2.03 (m, 1H), 1.22 (t, J=7.1Hz, 3H), 1.16-
0.89 (m, 6H), 0.96 (s, 9H)；MS(ESI+)m/z 421.1(M+H)+。
Example 66C
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) ammonia
Base) -5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -1,2- dicarboxylic acid esters
Will in the 5- (tert-butyl) in dichloroethanes (0.5mL)-Benzaldehyde,2-methoxy (0.022g, 0.113mmol) and
Example 66B (0.050g, 0.119mmol) is handled with sodium triacetoxy borohydride (0.034g, 0.159mmol), and will reaction
It is stirred at room temperature.After 130 minutes, mixture 0.5mL is saturated NaHCO3Aqueous solution processing, and mixture is vigorously stirred
30 minutes.These are mutually separated, and by water layer CH2Cl2Extraction is three times.By combined organic matter through Na2SO4It dries, filters simultaneously
It is concentrated in a vacuum to provide thick title compound, enters it in next reaction without further purification.MS(APCI+)m/
z 597.7(M+H)+。
Example 66D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Hydroxide will be used in the example 66C (0.067g, 0.113mmol) in tetrahydrofuran (0.9mL) and methanol (0.9mL)
Lithium (1M is aqueous) (0.9mL, 0.900mmol) processing, and reaction mixture is stirred overnight at 45 DEG C.After this, say that reaction is mixed
It closes object and is acidified to pH 1 with the aqueous HCl of 1N, and mixture is concentrated in a vacuum.By the way that excessive moisture is gone with acetonitrile azeotropic
It removes, then crude product is existed by reversed-phase HPLCC8(2)5umAXIA column (30mm × 75mm)
On purified.The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are 50mL/ minutes (0-1.0
Minute 5%A, 1.0-8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minute 100%A, 11.5-12.0 minutes linear ladders
Spend 95%-5%A), to obtain title compound (0.0232g, 36% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δ
Ppm 8.23-8.12 (m, 2H), 7.18 (dd, J=8.5,2.6Hz, 1H), 7.03 (m, 2H), 6.77 (d, J=8.6Hz, 1H),
5.34 (d, J=6.4Hz, 1H), 4.62 (m, 1H), 4.37 (d, J=1.5Hz, 1H), 3.75-3.60 (m, 2H), 3.53 (s,
3H), 3.34 (d, J=13.6Hz, 1H), 2.68 (s, 6H), 2.44 (m, 1H), 1.20 (s, 9H), 1.02 (m, 12H), 0.84 (d,
J=6.2Hz, 3H)；MS(ESI+)m/z 569.2(M+H)+。
Example 67
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 67A
Ethyl (2S, 3S, 4S, 5S) -4- ((5- (two rings [1.1.1] pentane -1- base) -2- methoxy-benzyl) amino) -3-
(tert-butyl) -1- ((R) -3,3- difluorocyclohex alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid esters
Example 69D (28.3mg, 0.065mmol) and example 51B (15.0mg, 0.074mmol) are dissolved in methanol (1mL)
And it stirs 3 hours at ambient temperature.It adds sodium cyanoborohydride (25.2mg, 0.401mmol), and will react in environment temperature
Under be stirred for 16 hours.Reaction mixture is diluted with dimethyl sulfoxide (1mL), filters and passes through reverse phase using ammonium acetate method
It is purified, to provide title compound (23.9mg, 59%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm
7.57 (s, 2H), 7.29 (d, J=24.7Hz, 3H), 6.92 (dd, J=8.3,2.2Hz, 1H), 6.74-6.68 (m, 2H), 5.18
(d, J=6.9Hz, 1H), 4.52 (d, J=3.0Hz, 1H), 4.11 (qd, J=7.1,1.3Hz, 2H), 3.51 (s, 3H), 3.44
(d, J=13.4Hz, 3H), 3.29 (d, J=13.7Hz, 1H), 2.49 (s, 1H), 2.36 (s, 1H), 1.94 (s, 6H), 1.90-
1.41 (m, 6H), 1.23-1.16 (m, 5H), 0.99 (s, 9H)；MS(ESI+)m/z 623(M+H)+。
Example 67B
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -
3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 67A (21.6mg, 0.035mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in trifluoroacetate
Title compound (18.5mg, 75%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.54 (s, 2H), 7.36
(t, J=7.4Hz, 2H), 7.28 (t, J=7.3Hz, 1H), 6.98 (dd, J=8.3,2.3Hz, 1H), 6.81-6.73 (m, 2H),
5.26 (d, J=7.0Hz, 1H), 4.51 (d, J=2.3Hz, 1H), 3.67-3.57 (m, 3H), 3.53 (s, 3H), 3.36 (d, J=
13.6Hz, 1H), 2.50 (s, 1H), 1.99 (s, 1H), 1.96 (s, 6H), 1.93-1.10 (m, 8H), 0.99 (s, 9H)；MS(ESI
+)m/z 595(M+H)+。
Example 68
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl } pyrrolidines -2- formic acid
Example 68A
(2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3-
Base) methyl) amino) -5- (2- isopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters
By 5- cyclobutyl -2- methoxyl group cigarette aldehyde (0.084g, 0.440mmol) and (2S, 3S, 4S, 5S) -1- tert-butyl 2- second
Base 4- amino -3- (tert-butyl) -5- (2- isopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters (example 61B；0.200g,
It 0.462mmol) is dissolved in dichloroethanes (2.2mL), then at sodium triacetoxy borohydride (0.131g, 0.616mmol)
Reason.Reaction is stirred at room temperature 30 minutes.Mixture 2.2mL is saturated NaHCO3Aqueous solution processing, and by mixture in room
It is vigorously stirred under temperature 15 minutes.Then these are mutually separated, and by water layer CH2Cl2Extraction is three times.Combined organic matter is passed through
Na2SO4It dries, filters and is concentrated in a vacuum.Silica gel chromatography (being eluted with 10 to 50% ethyl acetate-heptanes) provides mark
It inscribes compound 0.225g (84% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.86 (m, 1H), 7.72 (m,
1H), 7.23 (m, 3H), 7.12 (m, 1H), 5.13 (m, 1H), 4.33 (d, J=1.1Hz, 1H), 4.07 (m, 2H), 3.44 (m,
1H), 3.37 (s, 3H), 3.37-3.28 (m, 1H), 3.19 (m, 2H), 2.85 (m, 1H), 2.34 (m, 1H), 2.22-2.12 (m,
2H), 2.00-1.84 (m, 3H), 1.76 (m, 1H), 1.37-0.87 (m, 27H)；MS(ESI+)m/z 608.2(M+H)+。
Example 68B
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- isopropyl phenyl) pyrrolidines -2- formic acid esters
It will be in CH2Cl2Example 68A (0.224g, 0.369mmol) in (1.8mL) with trifluoroacetic acid (0.71mL,
It 9.21mmol) handles, and reaction is stirred at room temperature.After 2 hours, mixture is concentrated in a vacuum, and residue is inhaled
Close at CH2Cl2In, and washed twice and be washed with brine primary with the aqueous NaOH of 1N.By organic layer through Na2SO4It dries, filters,
And it is concentrated in a vacuum to provide title compound, 0.131g (70% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δ
Ppm 7.73 (d, J=2.4Hz, 1H), 7.64 (d, J=7.7Hz, 1H), 7.28-7.07 (m, 5H), 4.43 (d, J=4.9Hz,
1H), 4.14 (qd, J=7.0,2.2Hz, 2H), 3.66 (s, 1H), 3.63 (d, J=5.8Hz, 1H), 3.41-3.24 (m, 2H),
3.21-3.05 (m, 2H), 3.01 (m, 1H), 2.29-2.15 (m, 3H), 2.04-1.87 (m, 3H), 1.82 (m, 1H), 1.26-
1.13 (m, 9H), 0.98 (m, 9H)；MS(ESI+)m/z 508.2(M+H)+。
Example 68C
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3-
Base) methyl) amino) -5- (2- isopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters
Will the example 68B (0.025g, 0.049mmol) in dichloroethanes (0.2mL) with triethylamine (0.02mL,
It 0.143mmol) is handled with isopropyl chlorocarbonate (1M is in toluene) (0.09mL, 0.090mmol), and by mixture at 45 DEG C
It is stirred overnight.After this, mixture is cooled to room temperature, is then diluted with ethyl acetate, be washed twice with water and is washed with salt
It washs primary.By organic layer through Na2SO4It dries, filters, and is concentrated in a vacuum.Silica gel chromatography is (with 5% to 25% acetic acid second
Ester-heptane elution) title compound, 0.030g (quantitative) are provided.1HNMR (400MHz, dimethyl sulfoxide-d6)δppm 7.87
(m, 1H), 7.73 (m, 1H), 7.21 (m, 2H), 7.10 (m, 2H), 5.26 (d, J=6.3Hz, 1H), 4.62 (m, 1H), 4.42
(d, J=1.6Hz, 1H), 4.12 (q, J=7.1Hz, 2H), 3.56 (s, 3H), 3.47-3.35 (m, 3H), 3.17 (m, 1H),
3.04 (m, 1H), 2.37 (m, 1H), 2.26 (m, 2H), 1.98-1.83 (m, 4H), 1.19 (m, 6H), 1.07 (d, J=6.8Hz,
3H), 1.02 (s, 9H), 1.00 (d, J=6.1Hz, 3H), 0.81 (d, J=6.1,3H)；MS(ESI+)m/z 594.3(M+H)+。
Example 68D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Hydroxide will be used in the example 68C (0.029g, 0.049mmol) in tetrahydrofuran (0.4mL) and methanol (0.4mL)
Lithium (1M is aqueous) (0.4mL, 0.400mmol) processing, and reaction is stirred 5 hours at 45 DEG C.It is after this, mixture is cooling
It handles to room temperature and with the aqueous HCl of the 1N of 0.5mL, is then concentrated in a vacuum.By the way that excessive moisture is gone with acetonitrile azeotropic
It removes, and residue is existed by reversed-phase HPLCC8(2)5umAXIA column (30mm × 75mm)
On purified.The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are 50mL/ minutes (0-1.0
Minute 5%A, 1.0-8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minute 100%A, 11.5-12.0 minutes linear ladders
Spend 95%-5%A), to obtain title compound (0.0076g, 27% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δ
Ppm 7.85-7.75 (m, 2H), 7.29-7.07 (m, 4H), 5.28 (d, J=6.4Hz, 1H), 4.61 (p, J=6.2Hz, 1H),
4.39 (d, J=1.6Hz, 1H), 3.54 (d, J=14.1Hz, 1H), 3.57 (s, 3H), 3.54 (m, 1H), 3.42-3.36 (m,
2H), 3.23 (d, J=14.2Hz, 1H), 3.04 (t, J=6.7Hz, 1H), 2.41 (m, 1H), 2.30-2.20 (m, 2H), 2.05-
1.88 (m, 3H), 1.82 (m, 1H), 1.20 (d, J=6.7Hz, 3H), 1.08 (d, J=6.8Hz, 3H), 1.02 (s, 9H), 1.00
(d, J=6.2Hz, 3H), 0.80 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 566.3(M+H)+。
Example 69
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid
Example 69A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -1- ((R) -3- oxocyclohex alkyl carbonyl) -5- phenyl pyrazoline
Cough up alkane -2- formic acid esters
With
Example 69B
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -1- ((S) -3- oxocyclohex alkyl carbonyl) -5- phenyl pyrazoline
Cough up alkane -2- formic acid esters
By (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (core 7,
0.995g, 2.79mmol) it is dissolved in methylene chloride (10mL), and add triethylamine (0.972mL, 6.97mmol).Reaction is existed
It is cooling in ice bath, and solution of the 3- oxocyclohex alkane phosgene (0.537g, 3.35mmol) in 5mL methylene chloride is added dropwise.5 points
Zhong Hou removes ice bath, and adds the aqueous ammonium chloride (30mL) of saturation and the 200mL isopropyl acetate with 3mL ethyl alcohol.To have
The removal of machine object, is dried over sodium sulfate, and then it is used 80g silicagel column 5%-100% second to provide residue by concentration for filtering
Acetoacetic ester/heptane carries out purifying 40 minutes, to provide (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -1- ((R) -3-
Oxocyclohex alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid esters (0.554g, 1.246mmol, 44.7% yield).1H NMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.54 (s, 2H), 7.26 (q, J=7.5,7.0Hz, 3H), 5.71 (d, J=
9.0Hz, 1H), 5.62 (dd, J=8.8,3.6Hz, 1H), 4.72 (d, J=3.8Hz, 1H), 4.25 (q, J=7.1Hz, 2H),
3.06 (t, J=3.7Hz, 1H), 2.85-2.76 (m, 3H), 2.42-2.31 (m, 1H), 2.29-2.14 (m, 2H), 2.08 (d, J
=15.1Hz, 1H), 1.79 (s, 1H), 1.45 (d, J=9.8Hz, 1H), 1.28 (td, J=7.1,0.9Hz, 3H), 1.01 (s,
9H)；MS(APCI+)m/z 445(M+H)+.Another isomers is (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -
1- ((S) -3- oxocyclohex alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid esters (0.414g, 0.931mmol, 33.4% yield).1H NMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.54 (d, J=7.1Hz, 2H), 7.26 (q, J=7.8Hz, 3H), 5.70
(d, J=8.9Hz, 1H), 5.64 (dd, J=8.8,2.9Hz, 1H), 4.75 (d, J=3.4Hz, 1H), 4.24 (q, J=7.1Hz,
2H), 3.01 (t, J=3.2Hz, 1H), 2.91-2.76 (m, 1H), 2.33-2.16 (m, 2H), 2.10 (d, J=14.7Hz, 1H),
1.99-1.78 (m, 3H), 1.68 (tdd, J=12.8,8.7,4.6Hz, 1H), 1.61-1.45 (m, 1H), 1.28 (t, J=
7.1Hz, 3H), 1.01 (s, 9H)；MS(APCI+)m/z 445(M+H)+.Pass through the cyclohexyl acyl to the first eluting compounds (R)
The X-ray diffraction analysis of amine has determined absolute stereochemistry.
Example 69C
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((R) -3,3- difluorocyclohex alkyl carbonyl) -4- nitro -5- phenyl
Pyrrolidines -2- formic acid esters
To diethylaminosulfur trifluoride (DAST, 282 μ l, 2.133mmol) in the solution in methylene chloride (1.8mL)
Add the solution of example 69A (158mg, 0.355mmol) in methylene chloride (1.8mL).Reaction mixture is stirred at room temperature 4
Hour.Through 10 minutes by reaction 20mL saturation aqueous sodium bicarbonate quenching, and diluted with 75mL methylene chloride.By these layers point
From water layer being used 50mL methylene chloride extract again, and organic layer is purified using 12g silicagel column, with 5%-100% acetic acid
Ethyl ester/heptane elution, to provide (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((R) -3,3- difluorocyclohex alkyl carbonyl) -
4- nitro -5- Phenylpyrrolidine -2- formic acid esters (114mg, 0.244mmol, 68.7% yield).1H NMR (400MHz, dimethyl
Sulfoxide-d6) δ ppm 7.55 (s, 2H), 7.27 (d, J=7.9Hz, 3H), 5.77-5.53 (m, 2H), 4.72 (s, 1H), 4.25
(q, J=7.1Hz, 2H), 3.05 (t, J=3.5Hz, 1H), 2.05 (s, 1H), 1.94-1.44 (m, 4H), 1.39-1.10 (m,
5H), 1.01 (d, J=1.8Hz, 10H), 0.91-0.79 (m, 1H)；MS(APCI+)m/z 467(M+H)+。
Example 69D
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- ((R) -3,3- difluorocyclohex alkyl carbonyl) -5- phenyl
Pyrrolidines -2- formic acid esters
It will be added in 8mL pressure bottle in the example 69C (114mg, 0.244mmol) in tetrahydrofuran (3.5mL)
Through solvent washing after weighingIn 2800 aqueous slurry of nickel (344mg, 2.64mmol).By mixture argon cleaning 4
It is secondary, it is rinsed with hydrogen, and the shaken overnight at ambient temperature under 60psi hydrogen.Mixture is filtered by polypropylene screen, and
Solvent is removed in a vacuum, to provide (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((R) -3,3- difluorocyclohex alkane carbonyl
Base) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters.1H NMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.58 (s, 2H),
7.33 (t, J=7.5Hz, 2H), 7.25 (t, J=7.2Hz, 1H), 5.04 (d, J=7.2Hz, 1H), 4.39 (dd, J=7.9,
4.6Hz, 1H), 4.16 (q, J=7.1Hz, 2H), 3.70 (dd, J=7.3,4.3Hz, 1H), 2.07 (s, 1H), 2.02-1.89
(m, 1H), 1.91-1.59 (m, 2H), 1.60-1.46 (m, 1H), 1.37 (s, 1H), 1.27-1.21 (m, 3H), 1.22-1.04
(m, 1H), 1.00 (s, 9H), 0.89-0.71 (m, 3H)；MS(APCI+)m/z 467(M+H)+。
Example 69E
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -1- ((R) -3,3- difluorocyclohex alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid esters
By 5- cyclobutyl -2- methoxyl group cigarette aldehyde (0.021g, 0.109mmol) and example 69D (0.050g, 0.115mmol)
It is dissolved in dichloroethanes (0.6mL), and is handled with sodium triacetoxy borohydride (0.032g, 0.153mmol).It will react in room
Temperature stirring 30 minutes.Mixture 0.6mL is saturated NaHCO3Aqueous solution processing, and mixture is vigorously mixed at room temperature for 15
Minute.Then these are mutually separated, and water layer is extracted with dichloromethane three times.By combined organic matter through Na2SO4It is dry, mistake
It filters and is concentrated in a vacuum.Enter the title compound obtained in next reaction without other purifying.MS
(APCI+)m/z 612.6(M+H)+。
Example 69F
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) amino) -
1- ((R) -3,3- difluorocyclohex alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid
Hydroxide will be used in the example 69E (0.067g, 0.109mmol) in tetrahydrofuran (0.9mL) and methanol (0.9mL)
Lithium (1M is aqueous) (0.9mL, 0.900mmol) processing, and reaction is stirred overnight at 45 DEG C.After this, by reaction mixture
It is concentrated, is then further dried and with acetonitrile azeotropic in a vacuum.Then by residue 0.13mL trifluoroacetic acid and
The processing of 0.7mL ethyl acetate, and apply a solution on silicagel column, with (isocratic) elution of 4: 3: 1 heptane-ethyl acetates-ethyl alcohol.
Then the partially purified product of acquisition is further passed through reversed-phase HPLC to existC8(2)5um
It is purified on AXIA column (30mm × 75mm).The gradient of 0.1% trifluoroacetic acid (B) using acetonitrile (A) and in water, flow velocity are
50mL/ minutes (0-1.0 minutes 5%A, 1.0-8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minute 100%A,
11.5-12.0 minutes linear gradient 95%-5%A), to obtain title compound (0.0165g, 26% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.81 (d, J=2.5Hz, 1H), 758 (m, 2H), 7.32 (dt, J=28.9,
7.2Hz, 3H), 7.19 (d, J=2.4Hz, 1H), 5.29 (m, 1H), 4.54-4.46 (m, 1H), 3.67 (s, 3H), 3.65-3.52
(m, 2H), 3.36 (m, 2H), 2.44 (m, 1H), 2.33-2.21 (m, 2H), 2.07-1.52 (m, 11H), 1.21 (m, 2H), 0.99
(s, 9H)；MS(ESI+)m/z 584.2(M+H)+。
Example 70
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(6- tert-butyl -2- methoxypyridine -3-
Base) methyl] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 70A
(2S, 3R, 4S, 5S) -2- tert-butyl 1- isopropyl 3- (two rings [1.1.1] pentane -1- base) -4- nitro -5- phenyl
Pyrrolidines -1,2- dicarboxylic acid esters
At ambient temperature by example 56E (0.1g, 0.279mmol) and triethylamine (0.1mL, 0.717mmol) in toluene
The isopropyl chlorocarbonate (0.446mL, 0.446mmol) that solution in (0.1mL) is used in toluene is handled dropwise, is stirred at 45 DEG C
It mixes 3 hours, with 1N NH4The washing of OH (1mL) aqueous solution, and be concentrated to provide residue.Rough material is dissolved in 1mL methylene chloride
In, and be loaded on 12g column, with gradient elution 20 minutes of 0-40% ethyl acetate/heptane, with provide title compound (2S,
3R, 4S, 5S) -2- tert-butyl 1- isopropyl 3- (two rings [1.1.1] pentane -1- base) -4- nitro -5- Phenylpyrrolidine -1,2- bis-
Formic acid esters (91mg, 0.205mmol, 73.4% yield).1HNMR (400MHz, chloroform-d) δ ppm 7.58 (d, J=7.0Hz,
2H), 7.38-7.28 (m, 3H), 5.39 (d, J=41.2Hz, 1H), 5.05 (t, J=9.2Hz, 1H), 4.97-4.69 (m, 1H),
4.08 (s, 1H), 3.35 (t, J=9.1Hz, 1H), 2.56 (s, 1H), 1.84 (dd, J=9.6,1.9Hz, 3H), 1.76 (dd, J
=9.5,2.0Hz, 3H), 1.60 (s, 9H), 1.55 (s, 6H)；MS(DCI+)m/z 445(M+H)+。
Example 70B
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- (((6- (tert-butyl) -2- methoxypyridine -
3- yl) methyl) amino) -1- (isopropoxy carbonyl) -5- Phenylpyrrolidine -2- formic acid
It will be added in 8mL pressure bottle in the example 70A (90mg, 0.202mmol) in tetrahydrofuran (3mL)In 2800 aqueous slurry of nickel (334mg, 2.56mmol), with argon cleaning 4 times, rinsed with hydrogen, and in the hydrogen of 50psi
Shaken overnight under gas.Reaction is filtered and removes solvent in a vacuum, to provide desired product (2S, 3S, 4S, 5S)-
2- tert-butyl 1- isopropyl 4- amino -3- (two rings [1.1.1] pentane -1- base) -5- Phenylpyrrolidine -1,2- dicarboxylic acid esters
(75mg, 0.181mmol, 35.9% yield).1HNMR (400MHz, chloroform-d) δ ppm 7.61 (d, J=7.4Hz, 2H), 7.35
(t, J=7.5Hz, 2H), 7.27 (m, 1H), 4.86 (t, J=44.0Hz, 2H), 3.98 (bs, 1H), 3.41 (t, J=8.4Hz,
1H), 2.55 (s, 1H), 2.17 (t, J=8.5Hz, 1H), 1.84 (qd, J=9.7,1.7Hz, 6H), 1.57 (s, 9H), 1.20
(bs, 3H), 1.10 (bs, 3H)；MS(ESI+)m/z 415(M+H)+。
Example 70C
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(6- tert-butyl -2- methoxypyridine -3-
Base) methyl] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
To 6- (tert-butyl) -2- methoxyl group cigarette aldehyde (15.85mg, 0.082mmol), example 70B (34mg, 0.082mmol)
It is with zinc chloride (II) (11.18mg, 0.082mmol) molten in sodium acetate/acetate buffer (pH=4,1mL) in methanol
Sodium cyanoborohydride (7.73mg, 0.123mmol) is added in liquid, and reaction is stirred 2 hours at ambient temperature.Solvent is gone
It removes, and gained residue is subjected to chromatography using 12g silicagel column, with gradient elution 20 minutes of 0-60% ethyl acetate/heptane
(48mg, 0.080mmol, 92%).Mixture is dissolved in 2,2,2- trifluoroacetic acids (0.5mL, 6.49mmol), and in environment temperature
Degree lower stirring 5 hours.Solvent is removed, and rough material is absorbed in 0.5mL water, with the aqueous NaHCO of 1N3It is adjusted to pH 7,
Then it is extracted with 2mL diethyl ether.After the solvent is vaporised, thick residue is purified by using the chromatography of 4g silicagel column,
With gradient elution 15 minutes of 0-10% ethanol/methylene, to provide (2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -
1- yl) -4- (((6- (tert-butyl) -2- methoxypyridine -3- base) methyl) amino) -1- (isopropoxy carbonyl) -5- phenyl pyrazoline
Cough up alkane -2- formic acid (34mg, 0.063mmol, 77% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm 7.55-7.41
(m, 2H), 7.26 (ddd, J=7.6,5.8,2.2Hz, 3H), 7.23-7.16 (m, 1H), 6.80 (d, J=7.5Hz, 1H), 4.92
(d, J=7.3Hz, 1H), 4.62 (p, J=6.2Hz, 1H), 4.01 (d, J=6.1Hz, 1H), 3.74 (d, J=0.9Hz, 3H),
3.43 (s, 2H), 3.22 (t, J=7.0Hz, 1H), 2.44 (s, 1H), 2.37 (t, J=6.4Hz, 1H), 1.71 (d, J=
2.4Hz, 6H), 1.26 (d, J=0.7Hz, 9H), 1.07 (d, J=6.3Hz, 3H), 0.93 (d, J=6.2Hz, 3H)；MS(ESI
+)m/z 536(M+H)+。
Example 71
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 71A
(2S, 3R, 4S, 5S) -2- tert-butyl 1- isopropyl 3- (two rings [1.1.1] pentane -1- base) -5- (2- (dimethylamino
Base) pyridin-3-yl) -4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters
By (2S, 3R, 4S, 5S)-tert-butyl 3- (two rings [1.1.1] pentane -1- base) -5- (2- (dimethylamino) pyridine -
3- yl) -4- nitro-pyrrole alkane -2- formic acid esters (core 43,200mg, 0.497mmol) is dissolved in toluene (0.745mL), and adds three
Ethamine (0.173mL, 1.242mmol) is then slowly added the isopropyl chlorocarbonate being cooled to after about 10 DEG C in ice-water bath
(0.298mL, 0.596mmol) solution.With the addition of such rate, which makes (2 minutes) temperature during addition be maintained at ring
Border temperature is lower than environment temperature.After the completion of addition, reaction is removed from water-bath and is stirred 1 hour at ambient temperature.It will
Mixture is diluted with diethyl ether and saturation aqueous sodium bicarbonate is used to stir 20 minutes, these layers is separated later, by organic matter 1M
Aqueous HCl and salt water washing three times, are dried over sodium sulfate, and are filtered and are concentrated to provide rough material.Mixture is dissolved in 1mL heptane
In and be loaded on 12g column, with gradient elution 20 minutes of 0-60% ethyl acetate/heptane, to provide desired product
(2S, 3R, 4S, 5S) -2- tert-butyl 1- isopropyl 3- (two rings [1.1.1] pentane -1- base) -5- (2- (dimethylamino) pyridine -
3- yl) -4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters (225mg, 0.461mmol, 93% yield).1HNMR (400MHz, chloroform-
D) δ ppm 8.30 (d, J=5.0Hz, 2H), 7.04 (t, J=6.4Hz, 1H), 5.82 (s, 1H), 5.24 (dd, J=8.1,
5.7Hz, 1H), 4.88 (s, 1H), 4.30 (s, 1H), 3.17 (t, J=5.6Hz, 1H), 2.78 (s, 7H), 2.62 (s, 1H),
1.94-1.73 (m, 6H), 1.59 (d, J=2.9Hz, 12H), 1.28 (s, 4H), 1.00 (d, J=105.5Hz, 4H)；MS(ESI
+)m/z 489(M+H)+。
Example 71B
(2S, 3S, 4S, 5S) -2- tert-butyl 1- isopropyl 4- amino -3- (two rings [1.1.1] pentane -1- base) -5- (2-
(dimethylamino) pyridin-3-yl) pyrrolidines -1,2- dicarboxylic acid esters
Example 71A (224mg, 0.458mmol) and tetrahydrofuran (10mL) are added in 50mL pressure bottle-
2800 aqueous slurry of nickel (630mg, 4.83mmol), and vibrated 16 hours under 50psi hydrogen and environment temperature.Simultaneously by reaction filtering
Solvent is removed in a vacuum, to provide desired product (2S, 3S, 4S, 5S) -2- tert-butyl 1- isopropyl 4- amino -3-
(two rings [1.1.1] pentane -1- base) -5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -1,2- dicarboxylic acid esters (205mg,
0.447mmol, 98% yield).Material is dissolved in 1mL methylene chloride and is loaded on 12g column, with 0-7% methanol/dichloromethane
The gradient elution of alkane 20 minutes, to provide desired product (2S, 3S, 4S, 5S) -2- tert-butyl 1- isopropyl 4- amino -3-
(two rings [1.1.1] pentane -1- base) -5- (2- (dimethylamino) pyridin-3-yl) pyrrolidines -1,2- dicarboxylic acid esters (205mg,
0.447mmol, 98% yield).1HNMR (500MHz, chloroform-d) δ ppm 8.50 (d, J=7.6Hz, 1H), 8.28 (s, 1H),
7.08 (d, J=6.5Hz, 1H), 5.46 (dd, 1H), 5.01-4.74 (m, 1H), 4.00 (dd, 1H), 3.59 (t, J=8.6Hz,
1H), 2.86 (d, J=14.5Hz, 6H), 2.56 (s, 1H), 2.08 (t, J=8.9Hz, 1H), 1.92-1.79 (m, 6H), 1.59
(s, 9H), 1.36-1.20 (m, 3H), 1.02 (dd, 3H)；MS(ESI+)m/z 459(M+H)+。
Example 71C
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
To 5- (tert-butyl)-Benzaldehyde,2-methoxy (21mg, 0.104mmol), example 71B (47.6mg, 0.104mmol)
It is with zinc chloride (II) (14.14mg, 0.104mmol) molten in sodium acetate/acetate buffer (pH=4,1mL) in methanol
Sodium cyanoborohydride (9.78mg, 0.156mmol) is added in liquid, and reaction is stirred 2 hours at ambient temperature.Solvent is gone
It removes, and gained residue is subjected to chromatography using 12g silicagel column, with gradient elution 20 minutes of 0-70% ethyl acetate/heptane,
To provide intermediate (35mg, 0.055mmol, 53.1% yield).By mixture be dissolved in 2,2,2- trifluoroacetic acids (0.5mL,
In 6.49mmol), and stir 5 hours.Solvent is removed, and rough material is absorbed in 0.5mL water, with the aqueous NaHCO of 1N3It adjusts
Section is extracted to pH 7 with 2mL ether.After the solvent is vaporised, thick residue is carried out by using the chromatography of 4g silicagel column pure
Change, with gradient elution 15 minutes of 0-10% ethanol/methylene, to provide (2S, 3S, 4S, 5S) -3- (two rings [1.1.1] penta
Alkane -1- base) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2- (dimethylamino) pyridin-3-yl) -1- is (different
Propoxycarbonyl) pyrrolidines -2- formic acid (20mg, 0.035mmol, 33.3% yield).1HNMR (400MHz, dimethyl sulfoxide-
d6) δ ppm 8.20-8.10 (m, 2H), 7.12 (dd, J=8.5,2.6Hz, 1H), 6.97 (d, J=2.6Hz, 1H), 6.94 (dd,
J=7.6,4.7Hz, 1H), 6.73 (d, J=86Hz, 1H), 5.28 (d, J=6.2Hz, 1H), 4.63 (p, J=6.2Hz, 1H),
4.16 (d, J=2.6Hz, 1H), 3.56 (d, J=13.7Hz, 1H), 3.50 (s, 3H), 3.33 (d, J=13.8Hz, 1H),
3.31-3.27 (m, 1H), 2.62 (s, 6H), 2.56 (t, J=2.7Hz, 1H), 2.49 (s, 1H), 1.70 (t, J=1.4Hz,
6H), 1.20 (s, 9H), 1.03 (d, J=6.2Hz, 3H), 0.87 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 579(M+H)+。
Example 72
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 72A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- isopropyl phenyl) -1- (tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
By tetrahydro -2H- pyrans -2- formic acid (0.022g, 0.171mmol) in thionyl chloride (0.33mL, 4.52mmol)
Reflux 1 hour.Mixture is cooled to room temperature and then is concentrated in a vacuum, CH is used2Cl2Expel the thionyl chloride three of excessive residual
It is secondary.Then by residue with example 68B (0.087g, 0.171mmol) in CH2Cl2(0.34mL) and pyridine (0.17mL,
Solution processing in 2.102mmol).Reaction is stirred at room temperature overnight.It is after this, reaction mixture ethyl acetate is dilute
It releases, and is washed with water three times, be washed with brine primary.By organic layer through Na2SO4It dries, filters and is being concentrated in vacuo, then will
Gained residue is purified by silica gel chromatography, the elution of 0 to 40% ethyl acetate-heptane of use.Impurely obtain title compound
0.085g (80% yield), it is not further purified but is directly entered in next reaction.MS(ESI+)m/z 620.3(M+H)+。
Example 72B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
It will be in the example 72A (0.085g, 0.137mmol) and hydroxide in tetrahydrofuran (1.1mL) and methanol (1.1mL)
Lithium (1M is aqueous) (1.1mL, 1.100mmol) is stirred overnight at 45 DEG C.It is after this, reaction mixture is aqueous with 1.2mL 1N
HCl acidification, is then concentrated in a vacuum.By with acetonitrile azeotropic by excessive moisture removal, and by thus obtained remnants
Object is existed by reversed-phase HPLCC8(2)5umIt is purified on AXIA column (30mm × 75mm).Make
The gradient of 0.1% trifluoroacetic acid (B) with acetonitrile (A) and in water, flow velocity are 50mL/ minutes (0-1.0 minutes 5%A, 1.0-
8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minute 100%A, 11.5-12.0 minutes linear gradient 95%-5%A).
Obtain title compound, that is, second in the main peak eluted, 0.0167g (21% yield).1(400MHz, dimethyl are sub- by HNMR
Sulfone-d6) δ ppm 7.78 (d, J=2.4Hz, 1H), 7.65 (m, 1H), 7.30-7.15 (m, 3H), 7.07 (m, 1H), 5.40 (d, J
=6.5Hz, 1H), 4.87 (m, 1H), 4.02 (m, 1H), 3.84 (m, 1H), 3.59 (m, 1H), 3.56 (s, 3H), 3.44-3.26
(m, 3H), 3.06 (m, 2H), 2.51 (m, 1H), 2.31-2.21 (m, 2H), 1.96 (m, 3H), 1.84-1.77 (m, 2H), 1.60-
1.41 (m, 5H), 1.22 (d, J=6.7Hz, 3H), 107 (d, J=6.8Hz, 3H), 1.03 (s, 9H)；MS(ESI+)m/z
592.3(M+H)+。
Example 73
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Title compound (the main peak of elution is obtained from the purifying of the reversed-phase HPLC of reaction mixture described in example 72B
In first) (0.0166g, 21% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.86 (d, J=7.9Hz,
1H), 7.78 (d, J=2.4Hz, 1H), 7.35-7.21 (m, 2H), 7.17-7.13 (m, 2H), 5.62 (m, 1H), 4.63 (d, J=
1.5Hz, 1H), 3.74 (m, 1H), 3.61 (s, 3H), 3.65-3.50 (m, 2H), 3.43-3.33 (m, 1H), 3.19 (m, 2H),
3.10 (m, 2H), 2.43 (m, 1H), 2.31-2.20 (m, 2H), 2.02-1.90 (m, 3H), 1.83 (m, 1H), 1.68 (m, 1H),
1.53 (m, 1H), 1.43-1.33 (m, 4H), 1.27 (d, J=6.7Hz, 3H), 1.08 (d, J=6.8Hz, 3H), 1.02 (s,
9H)；MS(ESI+)m/z 592.2(M+H)+。
Example 74
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S*,
2R*, 4R*) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 74A
(2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) ammonia
Base) -5- (2- isopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters
By example 61B 5- (tert-butyl)-Benzaldehyde,2-methoxy (309mg, 1.607mmol) and zinc chloride (II)
The suspension of (159mg, 1.165mmol) in methanol/acetic acid/sodium acetate buffer (8mL) stirs under mild heating, so
3mL tetrahydrofuran is added afterwards.Solution is stirred 30 minutes, then adds sodium cyanoborohydride (110mg, 1.748mmol), and will
Reaction is stirred at room temperature 30 minutes.Solvent is removed under a nitrogen.Residue is diluted with aqueous bicarbonate and by thick object
Material is absorbed in 200mL methylene chloride.Organic matter is separated, is filtered by diatomite, is concentrated, and uses ethyl acetate/heptane
Solvent system is purified with 40g silicagel column, to obtain (2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -4-
((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2- isopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters (0.542g,
0.890mmol, 76% yield).1H NMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.88 (dd, J=7.9,1.4Hz, 1H),
7.23-7.13 (m, 2H), 7.08 (ddd, J=8.4,5.6,2.2Hz, 2H), 6.88 (d, J=2.6Hz, 1H), 6.66 (d, J=
8.5Hz, 1H), 5.21 (d, J=6.2Hz, 1H), 4.40 (d, J=1.5Hz, 1H), 4.11 (qd, J=7.1,1.9Hz, 2H),
3.49 (dd, J=13.5,6.5Hz, 1H), 3.41 (s, 3H), 3.38 (d, J=6.3Hz, 1H), 3.18 (dd, J=13.5,
6.2Hz, 1H), 3.02 (p, J=6.8Hz, 1H), 2.37 (d, J=1.4Hz, 1H), 1.20 (d, J=0.9Hz, 3H), 1.18 (d,
J=2.2Hz, 12H), 1.13 (s, 9H), 1.02 (d, J=8.3Hz, 13H)；MS(ESI+)m/z 609(M+H)+。
Example 74B
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2-
Isopropyl phenyl) pyrrolidines -2- formic acid esters
By (2S, 3S, 4S, 5S) -1- tert-butyl 2- ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl)
Amino) -5- (2- isopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters (0.455g, 0.70mmol) are dissolved in methylene chloride
In (2.88mL).It adds trifluoroacetic acid (1.358mL, 17.63mmol), and reaction is stirred at room temperature 4 hours.It will react dense
Contracing will be diluted with methylene chloride (200mL).Organic layer is washed with the aqueous NaOH of 1M (2x50mL), salt water (50mL), is passed through
Na2SO4It is dried, filtered and concentrated to provide (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy
Base benzyl) amino) -5- (2- isopropyl phenyl) pyrrolidines -2- formic acid esters (0.366g, 0.719mmol, 102% yield).1H
NMR (501MHz, chloroform-d) δ ppm 7.60 (d, J=7.5Hz, 1H), 7.31-7.26 (m, 2H), 7.24 (dt, J=7.5,
4.3Hz, 1H), 7.13 (dd, J=8.5,2.6Hz, 1H), 6.96 (d, J=2.5Hz, 1H), 6.61 (d, J=8.5Hz, 1H),
4.43 (d, J=4.4Hz, 1H), 4.31-4.20 (m, 2H), 3.72 (d, J=6.1Hz, 1H), 3.51 (d, J=13.2Hz, 1H),
3.46 (s, 3H), 3.14 (dd, J=4.5,1.3Hz, 1H), 3.07 (dt, J=13.7,3.7Hz, 2H), 2.21 (dd, J=6.0,
1.3Hz, 1H), 1.32 (t, J=7.1Hz, 3H), 1.26 (s, 9H), 1.23 (d, J=6.8Hz, 3H), 1.11 (d, J=6.9Hz,
3H), 1.07 (s, 9H)；MS(ESI+)m/z 508(M+H)+。
Example 74C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S*,
2R*, 4R*) -7- oxabicyclo [2.2.1]
Heptane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
To (1S, 2R, 4R) -7- oxabicyclo [2.2.1] heptane -2- formic acid [catalog number (Cat.No.) in methylene chloride (10mL)
EN300-77440] add in (58.1mg, 0.409mmol) and a few drop n,N-Dimethylformamide oxalyl dichloro (100mg,
0.786mmol, 0.4mL, 2M are in methylene chloride).Mixture stirs to 30 minutes at ambient temperature, under stress by solvent
Removal, and add fresh methylene chloride (5mL) and then remove again.Residue is dissolved in methylene chloride (2mL) and is added dropwise to
The methylene chloride of example 74B (160mg, 0.315mmol) and triethylamine (0.175mL, 1.258mmol) cooling in ice bath
In solution in (10mL).Mixture is stirred 1 hour in ice bath and it is made to be warmed to environment temperature.Add methylene chloride
(10mL).Mixture is washed with brine, through MgSO4It is dried, filtered and concentrated.By residue via color on 12g silicagel column
Spectrometry purifying, the ethyl acetate in heptane is with the gradient elution of 0-40%, and to provide title compound, (15% obtains 28mg
Rate).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.77-7.69 (m, 1H), 7.29-7.21 (m, 2H), 7.15-7.10
(m, 2H), 6.95 (d, J=2.5Hz, 1H), 6.68 (d, J=8.5Hz, 1H), 5.39 (d, J=6.4Hz, 1H), 4.56 (d, J=
3.0Hz, 1H), 4.41 (t, J=5.0Hz, 1H), 4.25 (s, 1H), 3.65 (d, J=13.6Hz, 1H), 3.45-3.37 (m,
2H), 3.39 (s, 3H), 3.29 (d, J=13.6Hz, 1H), 3.03 (q, J=6.8Hz, 1H), 2.54 (q, J=6.8Hz, 1H),
2.44 (s, 1H), 1.73-1.39 (m, 4H), 1.20 (d, J=6.8Hz, 3H), 1.18 (s, 9H), 1.02 (s, 9H), 0.99-
0.97 (m, 3H)；MS(ESI+)m/z 605.3(M+H)+。
Example 75
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Example 75A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -1-
((R) -3- oxocyclohex alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid esters
To (the R) -3- oxocyclohex alkane formic acid (223mg, 1.567mmol) and 2 drop N, N- in methylene chloride (10mL)
Oxalyl dichloro (1.567mL, 3.13mmol) (2M is in methylene chloride) is added in dimethylformamide, and by mixture in environment
At a temperature of stir 30 minutes.Solvent is removed under reduced pressure, and adds fresh methylene chloride and then removes again.Residue is molten
In methylene chloride (3mL), and it is added dropwise to (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((2- methoxyl group -4- (fluoroform
Base) benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters (example 65B, 500mg, 1.045mmol) and triethylamine (0.583mL,
In the solution of cooling (ice bath) 4.18mmol) in methylene chloride.Mixture is stirred at ambient temperature 1 hour.It will be anti-
It is diluted using methylene chloride and a small amount of ethyl alcohol, is washed with brine and is dried over sodium sulfate.After filtering, solvent is removed, and will be thick
Material is purified using 40g silicagel column, with ethyl acetate/heptane 5%-100% gradient elution 40 minutes, with provide (2S,
3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -1- ((R) -3- oxo ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid esters (0.471g, 0.782mmol, 74.8% yield).1HNMR (400MHz, two
Methyl sulfoxide-d6) δ ppm 7.58 (s, 2H), 7.28 (dt, J=27.6,7.5Hz, 3H), 7.15-6.97 (m, 3H), 5.23 (d,
J=6.9Hz, 1H), 4.51 (d, J=3.1Hz, 1H), 4.11 (q, J=7.1Hz, 2H), 3.64 (s, 3H), 3.47 (d, J=
14.1Hz, 2H), 3.38 (d, J=14.3Hz, 1H), 2.81-2.64 (m, 1H), 2.33 (ddd, J=14.6,10.1,1.1Hz,
2H), 2.26-2.11 (m, 2H), 2.08 (s, 1H), 1.77 (s, 1H), 1.57-1.30 (m, 1H), 1.19 (t, J=7.1Hz,
3H), 1.18-1.06 (m, 1H), 0.98 (s, 9H), 0.90-0.75 (m, 1H)；MS(APCI+)m/z 603(M+H)+。
Example 75B
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((R) -3,3- difluorocyclohex alkyl carbonyl) -4- ((2- methoxyl group -
4- (trifluoromethyl) benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters
To diethylaminosulfur trifluoride (DAST, 0.146mL, 1.105mmol) in the solution in methylene chloride (1mL)
Add the solution of example 75A (111mg, 0.184mmol) in 2mL methylene chloride.Reaction is stirred at room temperature overnight.It will reaction
Concentration 25%, then carefully with saturation aqueous sodium bicarbonate quenching.Rough material is subjected to chromatography using 24g silicagel column, is used
5%-10) 0% methyl tertiary butyl ether(MTBE)/heptane elution, with provide (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -1- ((R) -3,
3- difluorocyclohex alkyl carbonyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters
(62mg, 0.099mmol, 53.9% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.57 (s, 2H), 7.38-
7.20 (m, 3H), 7.14-6.98 (m, 3H), 5.20 (d, J=6.9Hz, 1H), 4.51 (d, J=3.1Hz, 1H), 4.12 (q, J=
7.1Hz, 2H), 3.64 (s, 3H), 3.47 (d, J=14.1Hz, 2H), 3.38 (d, J=14.2Hz, 1H), 2.62-2.50 (m,
1H), 2.33 (s, 1H), 2.07-1.91 (m, 1H), 1.93-1.44 (m, 3H), 1.32-1.21 (m, 2H), 1.19 (t, J=
7.1Hz, 3H), 1.16-1.07 (m, 1H), 1.02-0.96 (m, 9H), 0.89-0.80 (m, 1H)；MS(APCI+)m/z 625(M+
H)+。
Example 75C
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid
Hydrogen is added in the solution in methanol (1mL) and tetrahydrofuran (1.0mL) to example 75B (69mg, 0.110mmol)
Solution of the lithia (33mg, 1.378mmol) in 1mL water.Reaction is warmed 3 hours at 45 DEG C.By solvent in nitrogen stream
Lower removal, and the crude reaction aqueous HCl of 1N of 1.4mL is neutralized.Crude product is used into ethyl acetate/ethyl alcohol/heptane solvent system
System carries out chromatography using 12g silicagel column, to provide (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- ((R) -3,3- difluorocyclohex alkane
Carbonyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -5- Phenylpyrrolidine -2- formic acid hydrochloric acid (45mg,
0.071mmol, 64.4% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.68 (s, 2H), 7.31-7.12 (m,
3H), 7.11-6.96 (m, 3H), 5.11 (d, J=7.3Hz, 1H), 4.33 (s, 1H), 3.69 (s, 3H), 3.42 (d, J=
15.1Hz, 1H), 3.35 (s, 1H), 3.27 (d, J=15.1Hz, 1H), 2.40 (s, 1H), 1.93-1.84 (m, 1H), 1.83-
1.64 (m, 2H), 1.64-1.42 (m, 2H), 1.36-1.20 (m, 2H), 0.95 (s, 9H), 0.90-0.79 (m, 2H)；MS(APCI
+)m/z 597(M+H)+。
Example 76
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- (2- methoxypyridine -3- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 76A
(2S, 3R, 4S, 5S) -2- tert-butyl 1- isopropyl 3- (two rings [1.1.1] pentane -1- base) -5- (2- methoxyl group pyrrole
Pyridine -3- base) -4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters
Core 44 (250mg, 0.642mmol) is dissolved in toluene (1.2mL), and add triethylamine (0.224mL,
1.605mmol), be then slowly added after being cooled to about 10 DEG C in ice-water bath isopropyl chlorocarbonate (0.385mL,
0.770mmol) solution.With such rate addition, the rate make addition during (2-3 minutes) temperature be maintained at environment temperature or
Lower than environment temperature.After the completion of addition, reaction is removed from water-bath and is stirred 1 hour at ambient temperature.Diethyl ether is added,
And stir mixture 20 minutes together with saturation aqueous sodium bicarbonate, these layers are separated later, by the organic matter aqueous HCl of 1M
Three times with salt water washing, it is then dried over sodium sulfate, filters and be concentrated to provide thick residue.Mixture is dissolved in 1mL heptane
In and be loaded on 12g column, with gradient elution 20 minutes of 0-50% ethyl acetate/heptane, to provide desired product
(2S, 3R, 4S, 5S) -2- tert-butyl 1- isopropyl 3- (two rings [1.1.1] pentane -1- base) -5- (2- methoxypyridine -3- base) -
4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters (251mg, 0.528mmol, 82% yield).1HNMR (400MHz, chloroform-d) δ ppm
8.25 (s, 1H), 8.13-8.04 (m, 1H), 6.92 (dd, J=7.2,5.2Hz, 1H), 565 (s, 1H), 5.29-5.10 (m,
1H), 4.92 (s, 1H), 4.28 (s, 1H), 3.95 (d, J=1.0Hz, 3H), 3.18 (t, J=5.8Hz, 1H), 2.62 (s, 1H),
1.93-1.72 (m, 6H), 1.59 (s, 9H), 1.29 (s, 3H), 1.16-0.84 (m, 3H)；MS(ESI+)m/z 476(M+H)+。
Example 76B
(2S, 3S, 4S, 5S) -2- tert-butyl 1- isopropyl 4- amino -3- (two rings [1.1.1] pentane -1- base) -5- (2- first
Oxygroup pyridin-3-yl) pyrrolidines -1,2- dicarboxylic acid esters
Example 76A (250mg, 0.526mmol) and tetrahydrofuran (15mL) are added in 50mL pressure bottle-
2800 aqueous slurry of nickel (700mg, 5.37mmol), and vibrated 16 hours under 50psi hydrogen and environment temperature.Simultaneously by reaction filtering
Solvent is gone in a vacuum divided by providing desired product.Rough material is dissolved in 1mL methylene chloride and is loaded into 12g column
On, with gradient elution 20 minutes of 0-5% ethanol/methylene, to provide desired product (2S, 3S, 4S, 5S) -2- uncle
Butyl 1- isopropyl 4- amino -3- (two rings [1.1.1] pentane -1- base) -5- (2- methoxypyridine -3- base) pyrrolidines -1,2-
Dicarboxylic acid esters (187mg, 0.420mmol, 80% yield).1HNMR (400MHz, chloroform-d) δ ppm 8.37 (s, 1H), 8.07
(dd, J=4.9,1.9Hz, 1H), 6.95 (dd, J=7.3,5.0Hz, 1H), 5.31 (d, 1H), 4.88 (d, 1H), 3.98 (m,
4H), 3.55 (t, J=8.2Hz, 1H), 2.53 (s, 1H), 2.12 (t, J=8.3Hz, 1H), 1.83 (qd, J=9.6,1.7Hz,
6H), 1.55 (s, 9H), 1.24 (m, 3H), 0.96 (d, J=112.6Hz, 3H)；MS(ESI+)m/z 446(M+H)+。
Example 76C
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) first
Base] amino } -5- (2- methoxypyridine -3- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
To 5- (tert-butyl)-Benzaldehyde,2-methoxy (15.19mg, 0.079mmol), example 76B (32mg,
0.072mmol) and zinc chloride (II) (9.79mg, 0.072mmol) be in methanol sodium acetate/acetate buffer (pH=4,
Sodium cyanoborohydride (6.77mg, 0.108mmol) is added in solution in 1mL), and it is small to react stirring 2 at ambient temperature
When.Solvent is removed, and gained residue is subjected to chromatography using 12g silicagel column, with the gradient of 0-60% ethyl acetate/heptane
Elute 20 minutes (42mg, 0.068mmol, 94%).Rough material is dissolved in 2,2,2- trifluoroacetic acids (0.5mL, 6.49mmol),
And it stirs 16 hours.Solvent is removed, and rough material 0.5mL water is diluted.By the pH aqueous NaHCO of 1N3It is adjusted to pH 7,
And it is extracted with 2mL diethyl ether.After the solvent is vaporised, rough material is purified by using the chromatography of 4g silicagel column, uses 0-
The gradient elution of 10% ethanol/methylene 15 minutes, to provide (2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1-
Base) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (isopropoxy carbonyl) -5- (2- methoxypyridine -3- base)
Pyrrolidines -2- formic acid (32mg, 0.057mmol, 79% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm 8.13-
7.93 (m, 2H), 7.14 (dd, J=8.5,2.6Hz, 1H), 6.98 (d, J=2.5Hz, 1H), 6.94 (dd, J=7.1,5.2Hz,
1H), 6.75 (d, J=8.6Hz, 1H), 5.06 (s, 1H), 4.59 (d, J=29.3Hz, 1H), 4.06 (d, J=3.8Hz, 1H),
3.69 (s, 3H), 3.53 (d, J=13.6Hz, 1H), 3.46 (s, 3H), 3.38-3.32 (d, 1H), 3.19 (dd, J=6.6,
4.2Hz, 1H), 2.44 (s, 1H), 1.72-1.54 (m, 6H), 1.19 (s, 9H), 1.15-1.01 (m, 3H), 0.82 (d, J=
117.4Hz 3H)；MS(ESI+)m/z 566(M+H)+。
Example 77
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- { [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 77A
1- (tert-butyl) 2- ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- isopropyl phenyl) -4- (((2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidines -1,2- dicarboxylic acid esters
By example 61B (106.9mg, 0.247mmol) and 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (93.1mg,
It 0.454mmol) is dissolved in methanol (1mL) and stirs 1 hour at ambient temperature.Addition sodium cyanoborohydride (82.5mg,
1.313mmol), and by reaction it is stirred at ambient temperature 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filtering
And purified using ammonium acetate method by reverse phase, to provide title compound (105.7mg, 69%).1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.29-8.24 (m, 1H), 7.90-7.84 (m, 1H), 7.49 (d, J=2.4Hz, 1H),
7.25-7.15 (m, 2H), 7.12-7.05 (m, 1H), 5.23 (d, J=6.3Hz, 1H), 4.39 (d, J=1.6Hz, 1H), 4.12
(q, J=7.1Hz, 2H), 3.71 (s, 3H), 3.45 (dd, J=14.9,5.6Hz, 1H), 3.37 (d, J=6.4Hz, 1H), 3.24
(dd, J=15.1,5.2Hz, 1H), 3.06 (p, J=6.8Hz, 1H), 2.32 (d, J=1.5Hz, 1H), 1.23-1.16 (m,
6H), 1.13 (s, 9H), 1.09 (d, J=6.8Hz, 3H), 1.02 (s, 9H)；MS(ESI+)m/z 622(M+H)+。
Example 77B
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- isopropyl phenyl) -4- (((2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl) methyl) amino) pyrrolidines -2- formic acid esters
Example 77A (102.5mg, 0.165mmol) is dissolved in methylene chloride (1mL).Addition trifluoroacetic acid (0.5mL,
6.49mmol) and by reaction stir 16 hours at ambient temperature.It is in double trifluoroacetates to provide that reaction mixture, which is concentrated,
Title compound (124mg, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 8.47-8.41 (m,
1H), 7.85 (d, J=2.5Hz, 1H), 7.66 (d, J=7.8Hz, 1H), 7.43-7.33 (m, 2H), 7.23 (ddd, J=8.4,
6.9,1.9Hz, 1H), 4.57 (d, J=4.2Hz, 1H), 4.27-4.13 (m, 2H), 4.09 (s, 1H), 3.69 (s, 3H), 3.59
(d, J=14.4Hz, 1H), 3.44 (d, J=4.3Hz, 1H), 3.09 (d, J=14.5Hz, 1H), 2.95 (p, J=6.8Hz,
1H), 2.60 (d, J=7.2Hz, 1H), 1.23 (t, J=7.1Hz, 3H), 1.21-1.11 (m, 6H), 0.97 (s, 9H)；MS(ESI
+)m/z 522(M+H)+。
Example 77C
2- ethyl 1- isopropyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- isopropyl phenyl) -4- (((2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidines -1,2- dicarboxylic acid esters
Example 77B (102.5mg, 0.165mmol) is dissolved in methylene chloride (1.5mL), and adds triethylamine
(0.10mL, 0.717mmol) then adds isopropyl chlorocarbonate (0.10mL, 2M, 0.20mmol).It will react in environment temperature
Lower stirring 14 hours.Reaction is diluted with ethyl acetate (35mL), and is then washed with salt water (35mL) with the aqueous HCl of 1M (35mL)
It washs, is dried over sodium sulfate, filter and be concentrated to provide title compound (47.9mg, 95%).1(400MHz, dimethyl are sub- by HNMR
Sulfone-d6, 120 DEG C) and δ ppm 8.28 (d, J=2.1Hz, 1H), 7.86 (dd, J=7.8,1.4Hz, 1H), 7.50 (d, J=
2.4Hz, 1H), 7.27-7.13 (m, 2H), 7.08 (td, J=7.5,1.5Hz, 1H), 5.27 (d, J=6.4Hz, 1H), 4.62
(hept, J=6.2Hz, 1H), 4.41 (d, J=1.7Hz, 1H), 4.13 (q, J=7.0Hz, 2H), 3.71 (s, 3H), 3.45 (d,
J=15.0Hz, 1H), 3.38 (dd, J=6.4,0.9Hz, 1H), 3.24 (d, J=15.0Hz, 1H), 3.14-3.03 (m, 1H),
2.38-2.31 (m, 1H), 1.23-1.16 (m, 6H), 1.11 (d, J=6.8Hz, 3H), 1.04-0.97 (m, 12H), 0.81 (d, J
=6.2Hz, 3H)；MS(ESI+)m/z 608(M+H)+。
Example 77D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- { [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 77C (21.6mg, 0.035mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using ammonium acetate method by reverse phase, to provide title compound
(27.7mg, 61%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.32-8.23 (m, 1H), 7.87 (dd, J
=7.8,1.4Hz, 1H), 7.52 (d, J=2.5Hz, 1H), 7.26-7.14 (m, 2H), 7.08 (ddd, J=8.5,7.0,
1.6Hz, 1H), 5.25 (d, J=6.5Hz, 1H), 4.61 (hept, J=6.2Hz, 1H), 4.36 (d, J=1.8Hz, 1H), 3.70
(s, 3H), 3.48 (d, J=15.0Hz, 1H), 3.35 (d, J=6.5Hz, 1H), 3.23 (d, J=15.0Hz, 1H), 3.06 (p, J
=6.8Hz, 1H), 2.36 (t, J=1.1Hz, 1H), 1.20 (d, J=6.8Hz, 3H), 1.09 (d, J=6.8Hz, 3H), 1.04-
0.97 (m, 12H), 0.80 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 580(M+H)+。
Example 78
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid
Example 78A
(2S, 3R, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -5- (2- isopropoxypyrid -3- base) -4- nitro
Pyrrolidines -1,2- dicarboxylic acid esters
At ambient temperature, to (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- in methylene chloride (10mL)
Isopropoxypyrid -3- base) -4- nitro-pyrrole alkane -2- formic acid esters (core 13,2.00g, 5.27mmol) and triethylamine (5.88mL,
Isopropyl chlorocarbonate (3.88g, 31.6mmol) is added dropwise in 42.2mmol).Mixture is stirred overnight at ambient temperature, and is added
It adds methylene chloride (20mL) and water (10mL).Organic layer is washed with brine, through MgSO4It dries, filters, and is concentrated.In 80g
Title is provided via the purifying (ethyl acetate in heptane is with gradient elution of 0-40%) that chromatography carries out on silicagel column
Compound, 2.26g (92% yield).1HNMR (501MHz, chloroform-d) δ ppm 8.06 (dd, J=5.0,1.8Hz, 2H), 6.84
(dd, J=7.4,5.0Hz, 1H), 5.52 (d, J=7.9Hz, 1H), 5.39 (dd, J=14.6,7.8Hz, 2H), 4.90 (s,
1H), 4.72 (s, 1H), 4.36 (tq, J=7.1,3.4Hz, 2H), 2.96 (t, J=1.9Hz, 1H), 1.43 (d, J=6.1Hz,
3H), 1.41 (d, J=6.2Hz, 3H), 1.38 (t, J=7.1Hz, 3H), 1.32-1.13 (m, 3H), 1.10 (s, 9H), 0.98
(m, 3H)；MS(ESI+)m/z 466(M+H)+。
Example 78B
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -3- (tert-butyl) -5- (2- isopropoxypyrid -3- base)
Pyrrolidines -1,2- dicarboxylic acid esters
Replace example 10B with example 78A, title compound is prepared according to program described in example 10C.LC/MS(ESI
+)m/z 436.62(M+H)+。
Example 78C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid
By 2- methoxyl group -5- (trifluoromethyl) benzaldehyde [CAS#146539-83-5] (30.9mg, 0.152mmol), example
78B (60mg, 0.138mmol) and zinc chloride (II) (1.9mg, 0.014mmol) are sodium acetate/acetate buffer in methanol
Mixture in (pH=4,2mL) stirs 10 minutes at ambient temperature, to provide colourless solution.Add sodium cyanoborohydride
(13.13mg, 0.209mmol), and stir the mixture for 1 hour.Add methylene chloride (10mL) and water (10mL).By organic layer
It is washed with brine, through MgSO4It dries, filters, and is concentrated.Residue is purified on 12g silicagel column via chromatography, is used in
Ethyl acetate/methanol (10: 1) in heptane is eluted with 0-40%, to obtain (2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 3-
(tert-butyl) -5- (2- isopropoxypyrid -3- base) -4- ((2- methoxyl group -5- (trifluoromethyl) benzyl) amino) pyrrolidines -1,
2- dicarboxylic acid esters are dissolved in methanol (1.5mL) and the aqueous LiOH of 6M (0.5mL).It is small that mixture is stirred to 4 at 50 DEG C
When, pH is adjusted to 4-5 by adding the 4M HCl in dioxanes, and mixture is concentrated.Residue is dissolved in dichloromethane
In alkane (2mL) and filter.Mixture is purified on 4g silicagel column via chromatography, with methanol in methylene chloride with 0-
20% gradient elution, to provide title compound, 74mg (90% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm
8.01-7.94 (m, 2H), 7.46 (dd, J=8.6,2.3Hz, 1H), 7.23 (d, J=2.3Hz, 1H), 6.99 (d, J=8.6Hz,
1H), 6.85 (dd, J=7.4,4.9Hz, 1H), 5.23-5.15 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 4.71-4.60 (m,
1H), 4.35 (d, J=1.8Hz, 1H), 3.61 (d, J=1.0Hz, 3H), 3.55 (d, J=14.4Hz, 1H), 3.42 (d, J=
6.5Hz, 1H), 3.31 (d, J=14.4Hz, 1H), 2.64 (s, 1H), 2.32 (s, 1H), 1.28-1.23 (m, 3H), 1.13 (dd,
J=6.1,1.1Hz, 3H), 1.03 (d, J=6.2Hz, 3H), 0.97 (d, J=1.0Hz, 9H), 0.91 (d, J=6.2Hz, 3H)；
MS(ESI+)m/z 596.2(M+H)+。
Example 79
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- { [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid
Replace 2- methoxyl group -5- (trifluoromethyl) with 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde [CAS#124432-66-2]
Benzaldehyde prepares title compound according to program described in example 78C.1HNMR (400MHz, dimethyl sulfoxide-d6)δppm
8.30 (s, 1H), 8.01-7.96 (m, 2H), 7.53 (d, J=2.4Hz, 1H), 6.88-6.83 (m, 1H), 5.21 (p, J=
6.1Hz, 1H), 5.14 (d, J=6.6Hz, 1H), 4.65 (hept, J=6.2Hz, 1H), 4.35 (d, J=1.9Hz, 1H), 3.77
(s, 3H), 3.52 (d, J=15.1Hz, 1H), 3.42 (dd, J=66,1.2Hz, 1H), 3.30 (d, J=15.1Hz, 1H), 2.64
(m, 1H), 2.31 (s, 1H), 1.26 (d, J=5.9Hz, 3H), 1.15 (d, J=6.1Hz, 3H), 1.03 (d, J=6.2Hz,
3H), 0.98 (s, 9H), 0.91 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 597.2(M+H)+。
Example 80
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 80A
2- ethyl 1- isopropyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- (dimethylamino) pyridin-3-yl) -4-
((2- methoxyl group -5- (1- methyl-cyclobutyl) benzyl) amino) pyrrolidines -1,2- dicarboxylic acid esters
By example 66B (62.0mg, 0.147mmol) and 2- methoxyl group -5- (1- methyl-cyclobutyl) benzaldehyde (intermediate 5,
35.1mg, 0.172mmol) it is dissolved in methanol (1mL) and stirs 3 hours at ambient temperature.Add sodium cyanoborohydride
(429mg, 0.683mmol), and reaction is stirred for 16 hours at ambient temperature.By reaction mixture dimethyl sulfoxide
(1mL) dilution, is filtered and is purified using ammonium acetate method by reverse phase, to provide title compound (51.1mg, 57%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.19-8.12 (m, 2H), 6.98-6.89 (m, 2H), 6.75 (d, J
=2.5Hz, 1H), 6.70 (d, J=8.4Hz, 1H), 5.30 (d, J=6.3Hz, 1H), 4.61 (hept, J=6.2Hz, 1H),
4.39 (d, J=1.6Hz, 1H), 4.13 (qd, J=7.1,2.7Hz, 2H), 3.53-3.41 (m, 5H), 3.22 (d, J=
13.6Hz, 1H), 2.62 (s, 6H), 2.37-2.28 (m, 1H), 2.26-2.14 (m, 2H), 2.07-1.88 (m, 3H), 1.80-
1.66 (m, 1H), 1.32 (s, 3H), 1.19 (t, J=7.1Hz, 3H), 1.02-0.97 (m, 12H), 0.83 (d, J=6.2Hz,
3H)；MS(ESI+)m/z 609(M+H)+。
Example 80B
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5-
(1- methyl-cyclobutyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 80A (48.1mg, 0.079mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using ammonium acetate method by reverse phase, to provide title compound
(27.7mg, 61%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.21-8.11 (m, 2H), 6.97-6.91
(m, 2H), 6.79 (d, J=2.5Hz, 1H), 6.71 (d, J=8.4Hz, 1H), 5.29 (d, J=6.4Hz, 1H), 4.66-4.52
(m, 1H), 4.32 (d, J=1.5Hz, 1H), 3.56 (d, J=13.8Hz, 1H), 3.46 (s, 4H), 3.23 (d, J=13.8Hz,
1H), 2.61 (d, J=1.0Hz, 6H), 2.37-2.30 (m, 1H), 2.26-2.13 (m, 2H), 2.08-1.89 (m, 3H), 1.79-
1.66 (m, 1H), 1.32 (s, 3H), 1.00 (d, J=5.8Hz, 12H), 0.81 (d, J=6.2Hz, 3H)；MS(ESI+)m/z
581(M+H)+。
Example 81
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid
Replace 2- methoxyl group -5- (trifluoromethyl) benzaldehyde with 2- methoxyl group -4- (trifluoromethyl) benzaldehyde, according to example
Program described in 78C prepares title compound.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.00 (dd, J=4.9,
1.9Hz, 1H), 7.96 (dd, J=7.3,1.9Hz, 1H), 7.11 (t, J=6.1Hz, 2H), 7.05 (s, 1H), 6.87 (dd, J=
7.4,4.9Hz, 1H), 5.19 (hept, J=6.1Hz, 1H), 5.12 (d, J=6.5Hz, 1H), 4.65 (hept, J=6.2Hz,
1H), 4.36 (d, J=1.7Hz, 1H), 3.61 (s, 3H), 3.54 (d, J=14.5Hz, 1H), 3.43 (d, J=6.4Hz, 1H),
3.37 (d, J=14.5Hz, 1H), 2.64 (m, 1H), 2.32 (s, 1H), 1.26 (d, J=6.1Hz, 3H), 1.14 (d, J=
6.2Hz, 3H), 1.03 (d, J=6.2Hz, 3H), 0.97 (s, 9H), 0.91 (d, J=6.2Hz, 3H)；MS(ESI+)m/z
596.2(M+H)+。
Example 82
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 82A
(2S, 3R, 4S, 5S) -2- tert-butyl 1- isopropyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole
Alkane -1,2- dicarboxylic acid esters
By (2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid
Ester (core 9,1.5g, 3.84mmol) is dissolved in toluene (4.52mL), and adds triethylamine (1.338mL, 9.60mmol), is then delayed
Slow isopropyl chlorocarbonate (2.305mL, 4.61mmol) solution added after being cooled to about 10 DEG C in ice-water bath.With such
Rate addition, the rate make (2-3 minutes) temperature during addition be maintained at room temperature or lower than room temperature.When addition is completed, it will react
Mixture takes out from water-bath, is stirred at room temperature 1 hour, is diluted with diethyl ether, and stirs 20 with saturation aqueous sodium bicarbonate
Minute, these layers are separated later.Three times with the aqueous HCl of 1M and salt water washing by organic layer, it is then dried over sodium sulfate, filtering is simultaneously
Concentration.The rough material hot heptane of 20mL is ground, filtering, and filtrate is concentrated.Residue is loaded on 24g column, 0- is used
The gradient elution of 50% ethyl acetate/heptane 20 minutes, to provide desired product (2S, 3R, 4S, 5S) -2- tert-butyl 1-
Isopropyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters (1.55g, 3.25mmol,
85% yield).1H NMR (400MHz, chloroform-d) δ ppm 7.93 (d, J=7.9Hz, 1H), 7.25 (d, J=3.3Hz, 2H),
7.15 (ddd, J=8.4,5.3,3.3Hz, 1H), 5.61 (s, 1H), 5.26 (dd, J=8.5,1.5Hz, 1H), 4.83 (s, 1H),
4.60 (s, 1H), 3.12-2.98 (m, 2H), 1.63 (s, 9H), 1.40 (d, J=6.8Hz, 3H), 1.30 (d, J=6.8Hz,
3H), 1.11 (bs, 12H), 0.74 (s, 3H)；MS(ESI+)m/z 477(M+H)+。
Example 82B
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid esters
Example 82A (513.3mg, 1.075mmol) and tetrahydrofuran (8mL) are added in 20mL stainless steel pressure bottle
'sIn 2800 aqueous slurry of nickel (140mg, 1.075mmol), with argon cleaning 3 times, rinsed with hydrogen, and 50psi's
It is vibrated at ambient temperature under hydrogen 14.6 hours.Reaction is filtered and is concentrated to provide title compound (478mg, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.84 (dd, J=7.8,1.6Hz, 1H), 7.24 (dd, J=7.8,
1.5Hz, 1H), 7.17 (td, J=7.5,1.6Hz, 1H), 7.08 (td, J=7.5,1.6Hz, 1H), 5.16 (d, J=6.7Hz,
1H), 4.61 (p, J=6.2Hz, 1H), 4.19 (d, J=3.2Hz, 1H), 3.60 (dd, J=6.8,2.3Hz, 1H), 3.14 (p, J
=6.7Hz, 1H), 2.02 (t, J=2.7Hz, 1H), 1.48 (s, 9H), 1.27-1.17 (m, 6H), 1.04-0.97 (m, 12H),
0.83 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 447(M+H)+。
Example 82C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
By chloro- 6- methyl -4- (trifluoromethyl) pyridine of example 82B (48.9mg, 0.109mmol) and 2- (55.7mg,
It 0.285mmol) is dissolved in dimethyl sulfoxide (1mL).It adds potassium carbonate (106.3mg, 0.5mmol), and reaction is heated to 150
DEG C continue 15 hours.The reaction is cooled to room temperatures, are diluted with methanol (1mL), filter and pass through reverse phase using trifluoroacetic acid method
It is purified, to provide the title compound (27.8mg, 38%) for being in trifluoroacetate.1HNMR (400MHz, dimethyl sulfoxide-
d6, 120 DEG C) and δ ppm 8.03-7.95 (m, 1H), 7.14-7.02 (m, 3H), 6.47 (s, 1H), 6.17 (s, 1H), 5.54 (d, J
=9.6Hz, 1H), 5.39 (d, J=8.2Hz, 1H), 5.23-5.11 (m, 1H), 4.64 (hept, J=6.2Hz, 1H), 4.26
(d, J=5.7Hz, 1H), 3.08 (hept, J=6.8Hz, 1H), 2.34 (t, J=5.9Hz, 1H), 2.30 (s, 3H), 1.13 (d,
J=6.8Hz, 3H), 1.04 (d, J=6.3Hz, 3H), 1.02 (d, J=0.7Hz, 9H), 0.84 (d, J=6.3Hz, 3H), 0.80
(dd, J=6.7,0.9Hz, 3H)；MS(ESI+)m/z 550(M+H)+。
Example 83
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 83A
2- (tert-butyl) 1- isopropyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- isopropyl phenyl) -4- ((2- first
Oxygroup -5- (trifluoromethyl) benzyl) amino) pyrrolidines -1,2- dicarboxylic acid esters
By example 82B (48.2mg, 0.108mmol) and 2- methoxyl group -5- (trifluoromethyl) benzaldehyde (40.6mg,
It 0.199mmol) is dissolved in methanol (1mL), and stirs 1 hour at ambient temperature.Addition sodium cyanoborohydride (33.2mg,
0.528mmol), and by reaction it is stirred at ambient temperature 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filtering
And purified using ammonium acetate method by reverse phase, to provide title compound (40.6mg, 59%).1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.88 (dd, J=7.9,1.4Hz, 1H), 7.45-7.38 (m, 1H), 7.26-7.15
(m, 3H), 7.06 (td, J=7.4,1.6Hz, 1H), 6.94 (d, J=8.6Hz, 1H), 5.24 (d, J=6.3Hz, 1H), 4.62
(hept, J=6.2Hz, 1H), 4.30 (d, J=1.7Hz, 1H), 3.54 (d, J=0.9Hz, 3H), 3.47 (dd, J=14.1,
7.4Hz, 1H), 3.34 (dd, J=6.6,3.0Hz, 1H), 3.24 (dd, J=14.1,6.7Hz, 1H), 3.06 (h, J=6.9Hz,
1H), 2.33 (d, J=1.6Hz, 1H), 1.41 (d, J=0.8Hz, 9H), 1.20 (d, J=6.7Hz, 3H), 1.10 (d, J=
6.8Hz, 3H), 1.00 (d, J=2.4Hz, 12H), 0.83 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 635(M+H)+。
Example 83B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 83A (37.6mg, 0.059mmol) is dissolved in methylene chloride (1mL).Addition trifluoroacetic acid (0.5mL,
6.49mmol) and by reaction stir 16 hours at ambient temperature.By reaction concentration to provide in the titled of trifluoroacetate
It closes object (41.0mg, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.82 (dd, J=7.8,1.4Hz,
1H), 7.51 (dd, J=8.7,2.3Hz, 1H), 7.31-7.20 (m, 3H), 7.15 (td, J=7.4,1.8Hz, 1H), 7.01 (d,
J=8.6Hz, 1H), 5.29 (d, J=6.4Hz, 1H), 4.60 (hept, J=6.2Hz, 1H), 4.37 (d, J=1.7Hz, 1H),
3.69 (d, J=13.9Hz, 1H), 3.59-3.53 (m, 4H), 3.26 (d, J=14.0Hz, 1H), 3.04 (h, J=6.8Hz,
1H), 2.46 (s, 1H), 1.19 (d, J=6.7Hz, 3H), 1.10 (d, J=6.8Hz, 3H), 1.01 (s, 9H), 0.99 (d, J=
6.3Hz, 3H), 0.77 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 579(M+H)+。
Example 84
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 84A
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- isopropyl phenyl) -4- (((2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl) methyl) amino) -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Oxinane -2- formic acid (21.7mg, 0.167mmol) is dissolved in methylene chloride (1mL).Add oxalyl chloride
(35.2mg, 0.277mmol) then adds n,N-Dimethylformamide (10 μ L).Reaction is stirred at room temperature 3 hours, at this time
It is concentrated, is re-dissolved in methylene chloride (1mL) and is concentrated again.Residue is absorbed in methylene chloride (2x1mL), and
It is added to example 77B (97.0mg, 0.129mmol) and triethylamine (150 μ L, 1.076mmol) is molten in methylene chloride (1mL)
In liquid.Reaction is stirred 18 hours at ambient temperature.After this, mixture is concentrated and be dissolved in dimethyl sulfoxide/methanol (1:
1,2mL) it in, and is purified using ammonium acetate method by reverse phase.Title compound is the diastereoisomer of the first elution
(27.1mg, 33%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.29 (s, 1H), 7.89 (d, J=
7.9Hz, 1H), 7.50 (d, J=2.4Hz, 1H), 7.30 (d, J=7.7Hz, 1H), 7.23 (t, J=7.4Hz, 1H), 7.11 (t,
J=7.5Hz, 1H), 5.60 (s, 1H), 4.62 (d, J=1.5Hz, 1H), 3.74 (s, 3H), 3.54 (d, J=14.9Hz, 1H),
3.45 (d, J=6.7Hz, 1H), 3.22 (d, 1H), 3.15-3.08 (m, 4H), 2.37 (s, 1H), 1.72-1.32 (m, 6H),
1.27 (d, J=6.7Hz, 3H), 1.08 (d, J=6.7Hz, 3H), 1.01 (s, 9H)；MS(ESI+)m/z 634(M+H)+。
Example 84B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 84A (24.1mg, 0.038mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in double trifluoroacetates
Title compound (19.5mg, 62%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 829 (s, 1H), 7.89
(d, J=7.9Hz, 1H), 7.50 (d, J=2.4Hz, 1H), 7.30 (d, J=7.7Hz, 1H), 7.23 (t, J=7.4Hz, 1H),
7.11 (t, J=7.5Hz, 1H), 5.60 (s, 1H), 4.62 (d, J=1.5Hz, 1H), 3.74 (s, 3H), 3.54 (d, J=
14.9Hz, 1H), 3.45 (d, J=6.7Hz, 1H), 3.22 (d, 1H), 3.15-3.08 (m, 4H), 2.37 (s, 1H), 1.72-
1.32 (m, 6H), 1.27 (d, J=6.7Hz, 3H), 1.08 (d, J=6.7Hz, 3H), 1.01 (s, 9H)；MS(ESI+)m/z 606
(M+H)+。
Example 85
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 85A
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- isopropyl phenyl) -4- (((2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl) methyl) amino) -1- ((R)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Oxinane -2- formic acid (21.7mg, 0.167mmol) is dissolved in methylene chloride (1mL).Add oxalyl chloride
(35.2mg, 0.277mmol) then adds n,N-Dimethylformamide (10 μ L).Reaction is stirred at room temperature 3 hours, at this time
It is concentrated, is re-dissolved in methylene chloride (1mL) and is concentrated again.Residue is absorbed in methylene chloride (2x1mL), and
It is added to example 77B (97.0mg, 0.129mmol) and triethylamine (150 μ L, 1.076mmol) is molten in methylene chloride (1mL)
In liquid.Reaction is stirred 18 hours at ambient temperature.After this, mixture is concentrated and be dissolved in dimethyl sulfoxide/methanol (1:
1,2mL) it in, and is purified using ammonium acetate method by reverse phase.Title compound is the diastereoisomer of the second elution
(12.0mg, 15%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.28 (d, J=2.2Hz, 1H), 7.74
(s, 1H), 7.49 (d, J=2.5Hz, 1H), 7.25 (d, J=7.7Hz, 1H), 7.18 (t, J=7.5Hz, 1H), 7.04 (t, J=
7.5Hz, 1H), 5.39 (d, J=6.4Hz, 1H), 4.91 (s, 1H), 4.15 (q, J=7.1Hz, 2H), 3.96-3.76 (m, 2H),
3.70 (s, 3H), 3.49 (d, J=14.8Hz, 1H), 3.38 (d, J=6.5Hz, 1H), 3.27 (d, J=14.9Hz, 1H), 3.09
(p, J=6.8Hz, 1H), 2.50 (s, 1H), 1.79 (s, 1H), 1.63-1.32 (m, 6H), 1.23 (d, J=6.8Hz, 3H),
1.19 (t, J=7.1Hz, 3H), 1.10 (d, J=6.8Hz, 3H), 1.02 (s, 9H)；MS(ESI+)m/z 634(M+H)+。
Example 85B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 85A (9.0mg, 0.014mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in double trifluoroacetates
Title compound (8.1mg, 68%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 829 (d, J=2.3Hz,
1H), 7.71 (s, 1H), 7.53 (d, J=2.4Hz, 1H), 7.25 (d, J=7.7Hz, 1H), 7.18 (t, J=7.4Hz, 1H),
7.05 (t, J=7.5Hz, 1H), 5.39 (d, J=6.6Hz, 1H), 4.86 (s, 1H), 4.04-3.77 (m, 3H), 3.70 (d, J=
1.2Hz, 3H), 3.55 (d, J=14.8Hz, 1H), 3.38 (d, J=6.6Hz, 1H), 3.28 (d, J=14.8Hz, 1H), 3.08
(p, J=6.8Hz, 1H), 2.47 (s, 1H), 1.78 (s, 1H), 1.61-1.35 (m, 5H), 1.22 (d, J=6.7Hz, 3H),
1.08 (dd, J=6.8,1.1Hz, 3H), 1.01 (s, 9H)；MS(ESI+)m/z 606(M+H)+。
Example 86
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (3- chlorine
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 86A
(2S, 3R, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -5- (3- chlorphenyl) -4- nitro-pyrrole alkane -1,2-
Dicarboxylic acid esters
By (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (3- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters (core
29,2.003g, 5.64mmol) it is dissolved in toluene (6.64mL), and triethylamine (1.967mL, 14.11mmol) is added, then delay
Slow isopropyl chlorocarbonate (3.39mL, 6.77mmol) solution added after being cooled to about 10 DEG C in ice-water bath.With such
Rate addition, the rate make (2-3 minutes) temperature during addition be maintained at environment temperature or lower than environment temperature.Addition is completed
Afterwards, reaction is removed from water-bath and is stirred 1 hour at ambient temperature.It adds isopropyl chlorocarbonate (0.4mL), and will reaction
It is stirred at ambient temperature 30 minutes.Mixture will be diluted with diethyl ether, and stir 20 points with saturation aqueous sodium bicarbonate
Clock, separating layer, organic layer is washed twice with the aqueous HCl of 1M and salt water, is then dried over sodium sulfate later, filter and be concentrated with
Thick residue is provided, is loaded on 40g silicagel column, with gradient elution 40 minutes of 5%-100% ethyl acetate/heptane,
To provide impure product.The product is gone out from hexane precipitation, to provide (2S, 3R, 4S, 5S) -2- ethyl 1- isopropyl 3- (uncle
Butyl) -5- (3- chlorphenyl) -4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters (2.086g, 4.73mmol, 84% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.63 (t, J=1.5Hz, 1H), 7.48-7.41 (m, 1H), 7.29-7.20 (m,
2H), 5.64 (dd, J=8.7,3.0Hz, 1H), 5.44 (d, J=8.7Hz, 1H), 4.70 (p, J=6.2Hz, 1H), 4.51 (d, J
=3.6Hz, 1H), 4.25 (q, J=7.1Hz, 2H), 2.96 (t, J=3.3Hz, 1H), 1.30 (t, J=7.1Hz, 3H), 1.08
(d, J=6.2Hz, 3H), 1.01 (s, 9H), 0.95 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 441(M+H)+。
Example 86B
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -3- (tert-butyl) -5- (3- chlorphenyl) pyrrolidines -1,2-
Dicarboxylic acid esters
Example 86A (119mg, 0.270mmol) is dissolved in tetrahydrofuran (1349 μ L), and add zinc (200mg,
3.06mmol), then acetic acid (100 μ l, 1.747mmol) is added.Mixture is warmed to 40 DEG C and continues 3 hours, and in environment
At a temperature of stir 73 hours.Will reaction filtering, and solvent is gone divided by providing (2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4-
Amino -3- (tert-butyl) -5- (3- chlorphenyl) pyrrolidines -1,2- dicarboxylic acid esters (110mg, 0.268mmol, 99% yield).MS
(ESI+)m/z 411(M+H)+。
Example 86C
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) ammonia
Base) -5- (3- chlorphenyl) pyrrolidines -1,2- dicarboxylic acid esters
By example 86B (55mg, 0.134mmol), zinc chloride (II) (12mg, 0.088mmol) and 5- (tert-butyl) -2- first
Oxygroup benzaldehyde (33.5mg, 0.174mmol) is dissolved in sodium acetate/acetate buffer (pH=4,669 μ L) in methyl alcohol, and
It stirs 25 minutes at ambient temperature.It adds three sodium borohydride of cyano (12.62mg, 0.201mmol), and will react in environment temperature
Degree lower stirring 90 minutes.Solvent is removed under a nitrogen.By residue saturation aqueous sodium bicarbonate dilution, and rough material is inhaled
Close in methylene chloride, and purified using ethyl acetate/heptane solvent system with 12g silicagel column, with obtain (2S, 3S,
4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (3- chlorobenzene
Base) pyrrolidines -1,2- dicarboxylic acid esters (36mg, 0.043mmol, 32.1% yield).MS(ESI+)m/z 588(M+H)+。
Example 86D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (3- chlorine
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
By example 86C (36mg, 0.061mmol) and lithium hydroxide (0.2mL, 0.400mmol) be dissolved in methanol (0.2mL),
In tetrahydrofuran (0.200mL) and water (0.200mL).Reaction is warmed overnight at 45 DEG C.Solvent is removed under a nitrogen.It will
Residue is diluted with the aqueous HCl of 1N, and rough material is absorbed in methylene chloride, and uses ethyl acetate/ethyl alcohol/heptane solvent
System is purified with 4g silicagel column, to obtain (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxyl group
Benzyl) amino) -5- (3- chlorphenyl) -1- (isopropoxy carbonyl) pyrrolidines -2- formic acid (19mg, 0.034mmol, 55.4%
Rate).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.59 (t, J=1.8Hz, 1H), 7.42 (dt, J=7.6,1.6Hz,
1H), 7.28 (t, J=7.7Hz, 1H), 7.23 (ddd, J=7.9,2.1,1.3Hz, 1H), 7.13 (dd, J=8.5,2.6Hz,
1H), 6.94 (d, J=2.6Hz, 1H), 6.74 (d, J=8.5Hz, 1H), 4.98 (d, J=6.8Hz, 1H), 4.64 (p, J=
6.2Hz, 1H), 4.30 (d, J=2.4Hz, 1H), 3.58-3.48 (m, 4H), 3.44 (dd, J=6.8,1.9Hz, 1H), 3.30
(d, J=13.8Hz, 1H), 2.31 (t, J=2.3Hz, 1H), 1.99-1.84 (m, 1H), 1.20 (s, 9H), 1.05 (d, J=
6.2Hz, 3H), 0.96 (s, 9H), 0.90 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 559(M+H)+。
Example 87
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid
Replace 2- methoxyl group -5- (trifluoromethyl) benzaldehyde with 5- cyclobutyl -2- methoxyl group cigarette aldehyde, according in example 78C
The program of description prepares title compound.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.00 (dd, J=4.9,1.9Hz,
1H), 7.95 (dd, J=7.3,1.9Hz, 1H), 7.77 (d, J=2.4Hz, 1H), 7.15 (d, J=2.3Hz, 1H), 6.87 (dd,
J=7.4,4.9Hz, 1H), 5.24-5.16 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 4.66 (dq, J=12.3,6.1Hz,
1H), 4.36 (d, J=1.6Hz, 1H), 3.62 (d, J=0.9Hz, 3H), 3.50 (d, J=14.3Hz, 1H), 3.43 (d, J=
6.5Hz, 1H), 3.38 (q, J=8.5Hz, 1H), 3.26 (d, J=14.3Hz, 1H), 2.64 (m, 1H), 2.33 (s, 1H),
2.31-2.21 (m, 2H), 1.97 (dq, J=5.9,3.9,3.3Hz, 4H), 1.26 (d, J=6.0Hz, 3H), 1.13 (dd, J=
6.2,1.0Hz, 3H), 1.04 (d, J=6.2Hz, 3H), 0.98 (s, 9H), 0.91 (d, J=6.2Hz, 3H)；MS(ESI+)m/z
583.3(M+H)+。
Example 88
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl]
Methyl } amino) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid
Example 88A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- (o-tolyl) pyrroles
Alkane -2- formic acid esters
By ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -4- nitro -5- (o-tolyl) pyrrolidines -2- formic acid esters (core 1
(), 1.03g, 3.08mmol) it is dissolved in methylene chloride (10mL), and triethylamine (0.80mL, 5.74mmol) is added, then add
Add cyclohexanecarbonyl chloride (489.6mg, 3.34mmol).Reaction is stirred 16 hours at ambient temperature.By reaction dichloromethane
Alkane (50mL) dilution, and with the aqueous HCl of 1M (2x50mL) and salt water washing.Organic layer is dried over sodium sulfate, filter and is concentrated
To provide title compound (1.37g, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.83 (s,
1H), 7.17-7.05 (m, 3H), 5.71 (d, J=8.9Hz, 1H), 5.59 (dd, J=9.0,3.3Hz, 1H), 4.69 (d, J=
3.8Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 3.08 (t, J=3.5Hz, 1H), 2.41 (s, 3H), 2.05 (s, 1H), 1.83-
1.43 (m, 4H), 1.34-1.05 (m, 9H), 1.02 (s, 9H)；MS(ESI+)m/z 445(M+H)+。
Example 88B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (o-tolyl) pyrroles
Alkane -2- formic acid esters
Example 88A (1.37g, 3.08mmol) and tetrahydrofuran (50mL) are added in 250mL Stainless Steel pressure bottle
'sIn 2800 aqueous slurry of nickel (3.1g, 23.77mmol), and mixture is vibrated under 50psi hydrogen and environment temperature
16 hours.Reaction is filtered and is concentrated to provide title compound (1.28g, 100%).1HNMR (400MHz, dimethyl sulfoxide-
d6, 120 DEG C) δ ppm 7.87 (s, 1H), 7.20-7.07 (m, 3H), 5.20 (d, J=7.0Hz, 1H), 4.43 (d, J=3.5Hz,
1H), 4.17 (qd, J=71,0.9Hz, 2H), 3.74 (dd, J=7.1,3.0Hz, 1H), 2.34 (s, 3H), 2.10-1.93 (m,
2H), 1.70-1.58 (m, 2H), 1.47 (d, J=10.2Hz, 2H), 1.29-1.01 (m, 9H), 0.99 (s, 9H)；MS(ESI+)
m/z 415(M+H)+。
Example 88C
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -4- (trifluoromethyl)
Benzyl) amino) -5- (o-tolyl) pyrrolidines -2- formic acid esters
By example 88B (55.3mg, 0.133mmol) and 2- methoxyl group -4- (trifluoromethyl) benzaldehyde (43.7mg,
It 0.214mmol) is dissolved in methanol (1mL), and mixture is stirred at ambient temperature 1 hour.Add sodium cyanoborohydride
(41.6mg, 0.662mmol), and reaction is stirred for 16 hours at ambient temperature.Reaction is dilute with dimethyl sulfoxide (1mL)
It releases, filter and is purified using ammonium acetate method by reverse phase, to provide title compound (39.2mg, 49%).1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.85 (s, 1H), 7.17-7.00 (m, 6H), 5.23 (d, J=6.6Hz,
1H), 4.59 (d, J=1.8Hz, 1H), 4.12 (q, J=7.1Hz, 2H), 3.59 (d, J=1.1Hz, 3H), 3.54-3.41 (m,
2H), 3.32 (d, J=14.4Hz, 1H), 2.38-2.31 (m, 2H), 2.17 (s, 3H), 1.69-1.41 (m, 4H), 1.31-1.02
(m, 9H), 0.99 (s, 9H)；MS(ESI+)m/z 603(M+H)+。
Example 88D
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl]
Methyl } amino) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid
Example 88C (36.2mg, 0.060mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in trifluoroacetate
Title compound (37.3mg, 90%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.76 (s, 1H), 7.19-
7.10 (m, 5H), 7.07 (s, 1H), 5.27 (d, J=6.7Hz, 1H), 4.56 (d, J=1.6Hz, 1H), 3.67-3.59 (m,
4H), 3.57 (d, J=6.7Hz, 1H), 3.37 (d, J=14.2Hz, 1H), 2.43 (s, 1H), 2.29 (s, 1H), 2.21 (s,
3H), 1.69-1.44 (m, 4H), 1.32-1.02 (m, 6H), 1.00 (s, 9H)；MS(ESI+)m/z 575(M+H)+。
Example 89
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 89A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- isopropyl phenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
It will be in (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- isopropyl in dichloroethanes (2.7mL)
Base phenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters (0.240g, 0.557mmol) and 5- cyclobutyl -2-
Methoxyl group cigarette aldehyde (0.107g, 0.557mmol) is handled with sodium triacetoxy borohydride (0.165g, 0.780mmol), and will be anti-
It should be stirred at room temperature 45 minutes.Mixture 2.7mL is saturated NaHCO3Aqueous solution processing, and mixture is vigorously stirred 30
Minute.These are mutually separated, and by organic layer CH2Cl2Extraction is three times.By combined organic matter through Na2SO4It dries, filters simultaneously
It is being concentrated in vacuo, and thick residue is purified by silica gel chromatography, 5% to 30% ethyl acetate-CH of use2Cl2Elution, to obtain
Obtain title compound, 0.156g (46% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.90 (m, 1H), 7.73
(m, 1H), 7.25 (m, 2H), 7.16-7.02 (m, 2H), 5.61 (m, 1H), 4.72 (m, 1H), 4.22-4.03 (m, 3H), 3.85-
3.57 (m, 5H), 3.40 (m, 3H), 3.14 (m, 2H), 2.39 (m, 1H), 2.35-2.14 (m, 2H), 2.08-1.71 (m, 7H),
1.61 (m, 1H), 1.24-1.14 (m, 6H), 1.06 (d, J=6.8Hz, 3H), 1.02 (s, 9H)；MS(ESI+)m/z 606.4(M
+H)+。
Example 89B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Hydroxide will be used in the example 89A (0.156g, 0.258mmol) in tetrahydrofuran (2.6mL) and methanol (2.6mL)
Lithium (1M is aqueous) (2.6mL, 2.60mmol) processing, and reaction is stirred 1 hour at 45 DEG C.Then reaction mixture is used
The dilution of 3mL water, and pH 2 is acidified to the aqueous HCl of 1N.Then by aqueous mixture CH2Cl2Extraction 4 times, and having merging
Machine object is through Na2SO4It dries, filters and is concentrated in a vacuum.Crude product is purified by silica gel chromatography, 0 to 5% methanol of use-second
Acetoacetic ester elution, is then further purified with silica gel chromatography again, 0 to 2% methanol-ethyl acetate of use elution, to obtain title
Compound, 0.0393g (26% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.86 (d, J=7.9Hz, 1H),
7.75 (m, 1H), 7.31-7.18 (m, 2H), 7.15-7.07 (m, 2H), 5.62 (m, 1H), 4.64 (m, 1H), 4.11 (m, 1H),
3.63 (m, 2H), 3.57 (s, 3H), 3.50 (m, 1H), 3.38 (m, 2H), 3.22 (d, J=14.3Hz, 1H), 3.09 (m, 1H),
2.41 (m, 1H), 2.25 (m, 2H), 2.04-1.88 (m, 4H), 1.85-1.75 (m, 2H), 1.64 (m, 2H), 1.19 (d, J=
6.9Hz, 3H), 1.05 (dd, J=6.9Hz, 3H), 1.02 (s, 9H)；MS(APCI+)m/z 578.7(M+H)+。
Example 90
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -
5- (2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 90A
2- ethyl 1- isopropyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -4- nitro -5- (o-tolyl) pyrrolidines -1,2-
Dicarboxylic acid esters
By ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -4- nitro -5- (o-tolyl) pyrrolidines -2- formic acid esters (core
10,1.86g, 5.56mmol) it is dissolved in methylene chloride (10mL), and triethylamine (2.326mL, 16.69mmol) is added, then add
Chlorination isopropyl formate (3.34mL, 2M, 6.68mmol).Reaction is stirred 16 hours at ambient temperature.By reaction dichloro
Methane (50mL) dilution, and with the aqueous HCl of 1M (2x50mL) and salt water washing.Organic layer is dried over sodium sulfate, is filtered, then
Concentration.Residue is purified by silica gel chromatography (5% to 50% methyl tertiary butyl ether(MTBE) in heptane), it is titled to provide
It closes object (1.44g, 62%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.78 (dd, J=7.9,1.8Hz,
1H), 7.14-7.02 (m, 3H), 5.54 (d, J=2.7Hz, 2H), 4.64 (p, J=6.2Hz, 1H), 4.49 (d, J=4.0Hz,
1H), 4.26 (q, J=7.1Hz, 2H), 3.07 (dd, J=4.1,2.4Hz, 1H), 2.36 (s, 3H), 1.30 (t, J=7.1Hz,
3H), 1.05 (d, J=6.2Hz, 3H), 1.02 (s, 9H), 0.88 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 421(M+H)+。
Example 90B
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -3- (tert-butyl) -5- (o-tolyl) pyrrolidines -1,2-
Dicarboxylic acid esters
Example 90A (469mg, 1.115mmol) and tetrahydrofuran (8mL) are added in 20mL Stainless Steel pressure bottleIn 2800 aqueous slurry of nickel (986.7mg, 7.56mmol), and vibrated 18 hours under 60psi hydrogen and environment temperature.
Reaction is filtered and is concentrated to provide title compound (405.7mg, 93%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120
DEG C) δ ppm 7.79 (dd, J=7.9,2.0Hz, 1H), 7.15-7.03 (m, 3H), 5.05 (d, J=7.0Hz, 1H), 4.67-
4.56 (m, 1H), 4.29 (d, J=3.4Hz, 1H), 4.18 (q, J=7.1Hz, 2H), 3.68 (dd, J=6.9,2.8Hz, 1H),
2.29 (s, 3H), 2.07 (t, J=3.1Hz, 1H), 1.25 (td, J=7.1,0.7Hz, 3H), 1.03 (d, J=6.2Hz, 3H),
1.00 (d, J=0.7Hz, 9H), 0.87 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 391(M+H)+。
Example 90C
2- ethyl 1- isopropyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((6- methoxyl group -2,3- dihydro -1H- indenes -
5- yl) methyl) amino) -5- (o-tolyl) pyrrolidines -1,2- dicarboxylic acid esters
Example 90B (51.4mg, 0.132mmol) and 6- methoxyl group -5- indane formaldehyde (39.6mg, 0.225mmol) is molten
In methanol (1mL), and mixture is stirred at ambient temperature 1 hour.Addition sodium cyanoborohydride (43.7mg,
0.695mmol), and by reaction it is stirred at ambient temperature 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filtering
And purified using ammonium acetate method by reverse phase, to provide title compound (54.6mg, 75%).1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.80 (dq, J=4.3,2.5Hz, 1H), 7.09 (d, J=3.4Hz, 3H), 6.66 (s,
1H), 6.63 (s, 1H), 5.09 (d, J=6.5Hz, 1H), 4.62 (hept, J=6.2Hz, 1H), 4.40 (d, J=1.7Hz,
1H), 4.13 (q, J=7.1Hz, 2H), 3.46 (s, 3H), 3.41 (dd, J=6.6,1.1Hz, 1H), 3.37 (d, J=13.5Hz,
1H), 3.23 (d, J=13.6Hz, 1H), 2.77 (t, J=7.5Hz, 2H), 2.68 (t, J=7.4Hz, 2H), 2.35 (d, J=
1.7Hz, 1H), 2.13 (s, 3H), 2.02-1.93 (m, 2H), 1.21 (t, J=7.1Hz, 3H), 1.03 (d, J=6.2Hz, 3H),
0.99 (s, 9H), 0.87 (d, J=6.2Hz, 3H)；MS(ESI+)m/z 551(M+H)+。
Example 90D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -
5- (2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 90C (51.4mg, 0.094mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in trifluoroacetate
Title compound (56.3mg, 94%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.74-7.67 (m, 1H),
7.22-7.14 (m, 3H), 6.78 (s, 1H), 6.74 (s, 1H), 5.18 (d, J=6.6Hz, 1H), 4.61 (pd, J=6.2,
1.0Hz, 1H), 4.40 (d, J=1.5Hz, 1H), 3.75-3.64 (m, 2H), 3.52 (d, J=0.9Hz, 3H), 3.34 (d, J=
13.3Hz, 1H), 2.80 (t, J=7.4Hz, 2H), 2.71 (t, J=7.4Hz, 2H), 2.50 (s, 1H), 2.22 (s, 3H), 1.98
(p, J=7.4Hz, 2H), 1.05-1.02 (m, 3H), 1.01 (d, J=0.9Hz, 9H), 0.84 (d, J=6.2Hz, 3H)；MS
(ESI+)m/z 523(M+H)+。
Example 91
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 91A
2- ethyl 1- isopropyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- nitro-pyrrole alkane -
1,2- dicarboxylic acid esters
By ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- nitro-pyrrole alkane -2- formic acid esters
(core 14,1.32g, 3.66mmol) is dissolved in methylene chloride (10mL), and adds triethylamine (2.0mL, 14.35mmol), then
It adds isopropyl chlorocarbonate (7.0mL, 2M, 14.00mmol).Reaction is stirred 16 hours at ambient temperature.It will react with two
Chloromethanes (50mL) dilution, and with the aqueous HCl of 1M (2x50mL) and salt water washing.Organic layer is dried over sodium sulfate, filtering is simultaneously
Concentration.Residue is purified by silica gel chromatography (5% ethyl acetate in methylene chloride), to provide title compound
(1.30g, 79%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.74 (dd, J=7.5,1.7Hz, 1H),
7.16-7.04 (m, 2H), 6.98 (dd, J=7.4,1.6Hz, 1H), 5.88 (d, J=8.5Hz, 1H), 5.62 (dd, J=8.5,
2.1Hz, 1H), 4.72 (hept, J=6.2Hz, 0H), 4.51 (d, J=3.0Hz, 1H), 4.23 (q, J=7.1Hz, 2H), 2.98
(t, J=2.6Hz, 1H), 2.10 (ddd, J=13.6,8.3,5.5Hz, 1H), 1.26 (t, J=7.1Hz, 3H), 1.14 (d, J=
6.2Hz, 4H), 1.04-0.79 (m, 16H)；MS(ESI+)m/z 447(M+H)+。
Example 91B
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -3- (tert-butyl) -5- (2- cyclopropyl phenyl) pyrrolidines -
1,2- dicarboxylic acid esters
Example 91A (482.8mg, 1.081mmol) and tetrahydrofuran (9mL) are added in 20mL Stainless Steel pressure bottle
'sIn 2800 aqueous slurry of nickel (1.83g, 14.03mmol), and vibrated 18 hours under 50psi hydrogen and environment temperature.
Reaction is filtered and is concentrated to provide title compound (410.3mg, 91%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120
DEG C) δ ppm 7.83-7.77 (m, 1H), 7.16-7.08 (m, 2H), 7.05-7.00 (m, 1H), 5.50 (d, J=6.7Hz, 1H),
4.61 (hept, J=6.2Hz, 1H), 4.33 (d, J=2.9Hz, 1H), 4.20 (q, J=7.1Hz, 2H), 3.78 (dd, J=
6.7,2.1Hz, 1H), 2.10 (t, J=2.5Hz, 1H), 1.94 (tt, J=8.4,5.4Hz, 1H), 1.26 (t, J=7.0Hz,
3H), 1.05-0.99 (m, 12H), 0.91 (dddd, J=14.3,12.7,8.0,3.6Hz, 2H), 0.83 (d, J=6.2Hz,
3H), 0.70 (dtd, J=9.2,5.2,3.4Hz, 1H), 0.59 (dtd, J=8.5,5.3,3.2Hz, 1H)；MS(ESI+)m/z
417(M+H)+。
Example 91C
2- ethyl 1- isopropyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- (((2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl) methyl) amino) pyrrolidines -1,2- dicarboxylic acid esters
By example 91B (42.4mg, 0.102mmol) and 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (42.4mg,
It 0.207mmol) is dissolved in methanol (1mL) and stirs 1 hour at ambient temperature.Addition sodium cyanoborohydride (34.2mg,
0.544mmol), and by reaction it is stirred at ambient temperature 16 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filtering
And purified using ammonium acetate method by reverse phase, to provide title compound (40.9mg, 66%).1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) δ ppm 8.28 (t, J=1.6Hz, 1H), 7.87-7.81 (m, 1H), 7.49 (d, J=2.4Hz,
1H), 7.16-7.07 (m, 2H), 7.03-6.97 (m, 1H), 5.55 (d, J=6.4Hz, 1H), 4.62 (hept, J=6.2Hz,
1H), 4.43 (d, J=1.7Hz, 1H), 4.13 (q, J=7.1Hz, 2H), 3.72 (s, 3H), 3.46 (dd, J=15.1,6.2Hz,
2H), 3.29 (dd, J=15.0,6.0Hz, 1H), 2.37-2.32 (m, 1H), 1.77 (tt, J=8.3,5.4Hz, 1H), 1.19
(t, J=7.1Hz, 3H), 1.03-0.99 (m, 12H), 0.93-0.75 (m, 5H), 0.60-0.46 (m, 2H)；MS(ESI+)m/z
606(M+H)+。
Example 91D
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 91C (38.8mg, 0.064mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in double trifluoroacetates
Title compound (22.9mg, 44%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.30 (d, J=
2.3Hz, 1H), 7.86-7.77 (m, 1H), 7.54 (d, J=2.4Hz, 1H), 7.12 (hept, J=5.1Hz, 2H), 7.05-
6.97 (m, 1H), 5.57 (d, J=6.5Hz, 1H), 4.61 (hept, J=6.2Hz, 1H), 4.39 (d, J=1.6Hz, 1H),
3.73 (s, 3H), 3.57-3.46 (m, 2H), 3.31 (d, J=14.9Hz, 1H), 2.39 (s, 1H), 1.77 (ddd, J=13.8,
8.4,5.3Hz, 1H), 1.04-0.98 (m, 12H), 0.90 (td, J=8.9,2.7Hz, 1H), 0.86-0.72 (m, 4H), 0.60-
0.49 (m, 2H)；MS(ESI+)m/z 578(M+H)+。
Example 92
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid
Example 92A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -1- (cyclohexane carbo) -5- (o-tolyl) pyrrolidines -2- formic acid esters
By (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (o-tolyl) pyrroles
Alkane -2- formic acid esters (example 88B, 0.050g, 0.121mmol), 5- cyclobutyl -2- methoxyl group cigarette aldehyde (0.021g, 0.110mmol)
It is stirred at room temperature overnight in dichloroethanes (0.6mL) with sodium triacetoxyborohydride (0.033g, 0.153mmol).This it
Afterwards, mixture 0.6mL is saturated NaHCO3Aqueous solution processing, and mixture is vigorously stirred 30 minutes.These are mutually separated,
And water layer is extracted with dichloromethane three times.By combined organic matter through Na2SO4It dries, filters, and is concentrated in a vacuum, with
Thick title compound is provided, is directly entered it without further purification in next reaction.MS(APCI+)m/z 590.4(M+H)+。
Example 92B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid
By example 92A (0.065g, 0.110mmol) and lithium hydroxide (1M is aqueous) (0.9mL, 0.9mmol) in tetrahydro furan
Mutter (0.9mL) and methanol (0.9mL) in be stirred overnight at 45 DEG C.Reaction mixture is concentrated in a vacuum, then with 1mL's
The aqueous HCl processing of 1N, and be concentrated in a vacuum again.By residue by being further dried with acetonitrile azeotropic, then will
It is existed by reversed-phase HPLCC8(2)5umIt is purified on AXIA column (30mm × 75mm).Make
The gradient of 0.1% trifluoroacetic acid (B) with acetonitrile (A) and in water, flow velocity are 50mL/ minutes (0-1.0 minutes 5%A, 1.0-
8.5 minutes linear gradient 5%-100%A, 8.5-11.5 minute 100%A, 11.5-12.0 minutes linear gradient 95%-5%A),
To obtain title compound, 0.0238g (39% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.82 (d, J=
2.4Hz, 1H), 7.75 (m, 1H), 7.21-7.12 (m, 4H), 5.28 (d, J=6.8Hz, 1H), 4.59-4.53 (m, 1H), 3.67
(m, 1H), 3.64 (s, 3H), 3.57 (m, 1H), 3.45-3.28 (m, 2H), 2.45 (m, 1H), 2.31-2.22 (m, 3H), 2.22
(s, 3H), 2.06-1.91 (m, 3H), 1.89-1.80 (m, 1H), 1.65 (m, 2H), 1.51 (m, 2H), 1.26-1.04 (m, 5H),
1.00 (s, 9H), 0.84 (m, 1H)；MS(ESI+)m/z 562.3(M+H)+。
Example 93
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 93A
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3-
Base) methyl) amino) -5- (2- cyclopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters
By 5- cyclobutyl -2- methoxyl group cigarette aldehyde (0.025g, 0.130mmol), (2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl
Base 4- amino -3- (tert-butyl) -5- (2- cyclopropyl phenyl) pyrrolidines -1,2- dicarboxylic acid esters (example 91B, 0.0542g,
0.130mmol) stirred at room temperature in dichloroethanes (0.6mL) with sodium triacetoxy borohydride (0.039g, 0.182mmol)
It mixes overnight.Mixture 0.6mL is saturated NaHCO3Aqueous solution is handled and is vigorously stirred 30 minutes.These are mutually separated, and
Water phase is used into CH again2Cl2Extraction is three times.By combined organic matter through Na2SO4It dries, filters, and is concentrated in a vacuum, to mention
For thick title compound, it is directly entered it without further purification in next reaction.MS(APCI+)m/z 592.7(M+H)+。
Example 93B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
By example 93A (0.077g, 0.130mmol) and lithium hydroxide (1M is aqueous) (1.0mL, 1.0mmol) at 45 DEG C
It is stirred overnight in tetrahydrofuran (1.0mL) and methanol (1.0mL).By mixture with the aqueous HCl acidification of 1N of 1.2mL and true
Aerial concentration.By removing excessive moisture with acetonitrile azeotropic.Then residue is existed by reversed-phase HPLCC8(2)5umIt is purified on AXIA column (30mm × 75mm).Using acetonitrile (A) and in water
The gradient of 0.1% trifluoroacetic acid (B), flow velocity are 50mL/ minutes (0-1.0 minutes 5%A, 1.0-8.5 minutes linear gradient 5%-
100%A, 8.5-11.5 minutes 100%A, 11.5-12.0 minutes linear gradient 95%-5%A), to obtain title compound,
0.0146g (20% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.83-7.74 (m, 2H), 7.21-7.11 (m,
3H), 7.08-7.01 (m, 1H), 5.58 (d, J=6.4Hz, 1H), 4.61 (hept, J=6.2Hz, 1H), 4.41 (d, J=
1.5Hz, 1H), 3.59 (s, 3H), 3.63-3.53 (m, 2H), 3.44-3.35 (m, 1H), 3.30 (d, J=14.3Hz, 1H),
2.43 (d, J=1.4Hz, 1H), 2.31-2.20 (m, 2H), 2.03-1.91 (m, 3H), 1.85 (m, 1H), 1.75 (m, 1H),
1.03-1.00 (m, 12H), 0.95-0.72 (m, 5H), 0.54 (dq, J=4.6,2.6Hz, 2H)；MS(ESI+)m/z 564.3(M
+H)+。
Example 94
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 94A
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3-
Base) methyl) amino) -5- (o-tolyl) pyrrolidines -1,2- dicarboxylic acid esters
By 5- cyclobutyl -2- methoxyl group cigarette aldehyde (0.025g, 0.131mmol), (2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl
Base 4- amino -3- (tert-butyl) -5- (o-tolyl) pyrrolidines -1,2- dicarboxylic acid esters (example 90B, 0.0512g,
0.131mmol) stirred at room temperature in dichloroethanes (0.6mL) with sodium triacetoxy borohydride (0.039g, 0.184mmol)
It mixes overnight.After this, mixture 0.6mL is saturated NaHCO3Aqueous solution processing, and be vigorously stirred 30 minutes.By these phases point
From, and water phase is used into CH again2Cl2Extraction is three times.By combined organic matter through Na2SO4It dries, filters, and dense in a vacuum
Contracting, to provide thick title compound, is directly entered it without further purification in next reaction.MS(APCI+)m/z 566.7
(M+H)+。
Example 94B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
By example 94A (0.074g, 0.131mmol) and lithium hydroxide (1M is aqueous) (1.1mL, 1.1mmol) in tetrahydro furan
Mutter (1.1mL) and methanol (1.1mL) in be stirred overnight at 45 DEG C.After this, by the aqueous HCl acid of 1N of mixture 1.2mL
Change and is concentrated in a vacuum.By removing excessive moisture with acetonitrile azeotropic.Then residue is existed by reversed-phase HPLCC8(2)5umIt is purified on AXIA column (30mm × 75mm).Using acetonitrile (A) and in water
The gradient of 0.1% trifluoroacetic acid (B), flow velocity are 50mL/ minutes (0-1.0 minutes 5%A, 1.0-8.5 minutes linear gradient 5%-
100%A, 8.5-11.5 minutes 100%A, 11.5-12.0 minutes linear gradient 95%-5%A), to obtain title compound,
0.0178g (25% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.84-7.74 (m, 2H), 7.21-7.10 (m,
4H), 5.14 (d, J=6.6Hz, 1H), 4.61 (h, J=6.2Hz, 1H), 4.39 (d, J=1.8Hz, 1H), 3.64 (s, 3H),
3.62-3.50 (m, 3H), 3.47-3.33 (m, 1H), 2.43 (m, 1H), 2.33-2.21 (m, 2H), 2.18 (s, 3H), 2.06-
1.88 (m, 3H), 1.84 (m, 1H), 1.03 (d, J=6.2Hz, 3H), 1.00 (s, 9H), 0.85 (d, J=6.2Hz, 3H)；MS
(ESI+)m/z 538.2(M+H)+。
Example 95
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 95A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro -1- ((S)-tetrahydrofuran -
2- carbonyl) pyrrolidines -2- formic acid esters
(S)-tetrahydrofuran -2- formic acid (248.1mg, 2.137mmol) is dissolved in methylene chloride (10mL).Add oxalyl
Chlorine (436.5mg, 3.44mmol) then adds n,N-Dimethylformamide (25 μ L).It is small that stirring 3 at ambient temperature will be reacted
When, it is concentrated at this time, is re-dissolved in methylene chloride (1mL) and is concentrated again.Residue is absorbed in methylene chloride
In (3x1mL), and core 8 (502.5mg, 1.386mmol) and triethylamine (500 μ L, 3.59mmol) are added in methylene chloride
In solution in (10mL).Reaction is stirred 17 hours at ambient temperature.After this, by mixture CH2Cl2(100mL) is dilute
It releases, and with being saturated aqueous NaHCO3It washes twice, and is washed with brine primary.By organic layer through Na2SO4It is dried, filtered and concentrated
To provide title compound (535.0mg, 84%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.91 (d, J
=7.9Hz, 1H), 7.29-7.17 (m, 2H), 7.07 (t, J=7.3Hz, 1H), 6.07 (s, 1H), 5.54 (dd, J=9.0,
2.7Hz, 1H), 4.81 (s, 1H), 4.26 (q, J=7.1Hz, 2H), 3.75-3.55 (m, 2H), 3.26 (hept, J=7.0Hz,
1H), 3.03 (t, J=3.2Hz, 1H), 2.91 (s, 1H), 2.01-1.89 (m, 2H), 1.86-1.57 (m, 2H), 1.36-1.14
(m, 9H), 1.03 (s, 9H)；MS(ESI+)m/z 461(M+H)+。
Example 95B
Ethyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -5- (2- isopropyl phenyl) -1- ((S)-tetrahydrofuran -
2- carbonyl) pyrrolidines -2- formic acid esters
Example 95A (535.0mg, 1.162mmol) and tetrahydrofuran (10mL) are added in 50mL Stainless Steel pressure bottle
InIn 2800 aqueous slurry of nickel (1.71g, 13.11mmol), and mixture is vibrated at 50psi hydrogen and 50 DEG C
26 hours.Reaction is filtered and is concentrated to provide title compound (404.3mg, 81%).1(400MHz, dimethyl are sub- by HNMR
Sulfone-d6, 120 DEG C) and δ ppm 7.90 (d, J=7.8Hz, 1H), 7.29 (dd, J=7.8,1.4Hz, 1H), 7.21 (t, J=
7.4Hz, 1H), 7.13 (t, J=7.5Hz, 1H), 5.57 (s, 1H), 4.53 (s, 1H), 4.18 (t, J=7.1Hz, 2H), 4.13-
3.97 (m, 1H), 3.73-3.63 (m, 2H), 3.63-3.53 (m, 1H), 3.20 (p, J=6.7Hz, 1H), 2.06 (t, J=
2.9Hz, 1H), 1.83-1.70 (m, 1H), 1.62 (s, 1H), 1.32-1.14 (m, 11H), 1.00 (s, 9H)；MS(ESI+)m/z
431(M+H)+。
Example 95C
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- (((2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl) methyl) amino) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
By example 95B (211.6mg, 0.491mmol) and 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (158.3mg,
It 0.771mmol) is dissolved in methanol (4.5mL).It adds sodium cyanoborohydride (107.1mg, 1.704mmol), and reaction is existed
Stirred at ambient temperature 17 hours.Reaction is diluted with methylene chloride (50mL), and sudden with saturation aqueous sodium bicarbonate (50mL)
It goes out, and stirs 30 minutes.Organic layer is concentrated and extracts water layer with methylene chloride (2x50mL).Combined organic layer is passed through
Na2SO4It is dried, filtered and concentrated.Residue is purified using ammonium acetate method by reverse phase, to provide title compound
(119.2mg, 39%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.27 (t, J=1.6Hz, 1H), 7.90
(d, J=7.8Hz, 1H), 7.49 (d, J=2.4Hz, 1H), 7.25 (dd, J=19.8,7.5Hz, 2H), 7.10 (t, J=
7.4Hz, 1H), 5.64 (s, 1H), 4.71 (s, 1H), 4.11 (q, J=7.1Hz, 2H), 3.71 (d, J=1.3Hz, 3H), 3.67
(q, J=7.1,6.6Hz, 1H), 3.60 (s, 1H), 3.52-3.38 (m, 2H), 3.24 (dd, J=14.9,7.0Hz, 1H), 3.12
(p, J=6.9Hz, 1H), 2.36 (s, 1H), 2.05-1.93 (m, 2H), 1.84-1.55 (m, 2H), 1.22 (dd, J=6.9,
1.1Hz, 3H), 1.18 (td, J=7.1,0.9Hz, 3H), 1.09 (dd, J=6.9,1.3Hz, 3H), 1.03-0.99 (m, 9H)；
MS(ESI+)m/z 620(M+H)+。
Example 95D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -1- [(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 95C (116.2mg, 0.188mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using ammonium acetate method by reverse phase, to provide title compound
(61.7mg, 56%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.26 (s, 1H), 7.98 (d, J=
7.8Hz, 1H), 7.47 (d, J=2.4Hz, 1H), 7.24 (d, J=7.8Hz, 1H), 7.19 (t, J=7.5Hz, 1H), 7.07 (t,
J=7.5Hz, 1H), 5.59 (s, 1H), 4.55 (s, 1H), 3.74 (s, 3H), 3.69 (t, J=7.0Hz, 1H), 3.63-3.55
(m, 2H), 3.47 (d, J=15.2Hz, 1H), 3.38 (d, J=6.8Hz, 1H), 3.22-3.07 (m, 2H), 2.39 (s, 1H),
1.95 (dt, J=8.4,5.4Hz, 1H), 1.79 (dt, J=14.1,6.7Hz, 1H), 1.73-1.55 (m, 2H), 1.22 (d, J=
6.7Hz, 3H), 1.09 (d, J=6.8Hz, 3H), 1.00 (s, 9H)；MS(ESI+)m/z 592(M+H)+。
Example 96
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- ring
PropyIpyridine -3- base) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 96A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- cyclopropyl pyridine -3- base) -4- nitro -1- ((S)-tetrahydro
Furans -2- carbonyl) pyrrolidines -2- formic acid esters
At ambient temperature, to (S)-tetrahydrofuran -2- formic acid (321mg, 277mmol) in methylene chloride (10mL)
Add oxalyl dichloro in a few drop n,N-Dimethylformamide (527mg, 4.15mmol, 2.2mL, 2M are in methylene chloride).It will
Mixture stirs 30 minutes, and solvent is removed under stress, and adds fresh methylene chloride (5mL) and then remove again.It will be residual
Excess is dissolved in methylene chloride (3mL), and is added dropwise to (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- cyclopropyl pyridine -
3- yl) -4- nitro-pyrrole alkane -2- formic acid esters (core 19,500mg, 1.383mmol) and triethylamine (0.771mL, 5.53mmol) exist
In the solution in methylene chloride (10mL) in ice bath.Mixture is stirred 30 minutes in ice bath, then it is made to be warmed to room
Temperature.Add methylene chloride (10mL) and the aqueous NH of saturation4Cl (10mL), and organic layer is washed with brine, through MgSO4It is dry, mistake
It filters and is concentrated to provide title compound 620mg (98%), it is used in next step without further purification.LC/MS
(APCI+)m/z 460.23(M+H)+。
Example 96B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- cyclopropyl pyridine -3- base) -1- ((S)-tetrahydro
Furans -2- carbonyl) pyrrolidines -2- formic acid esters
Replace example 10B with example 96A (600mg, 1.306mmol), title is prepared according to program described in example 10C
Compound (489mg, 87% yield).LC/MS(APCI+)m/z 430.23(M+H)+。
Example 96C
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2- cyclopropyl
Yl pyridines -3- base) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid
By 5- (tert-butyl) -2- methoxybenzene first in the sodium acetate/acetate buffer (pH=4,2mL) being in methanol
Aldehyde (29.5mg, 0.154mmol), example 96B (60mg, 0.140mmol) and zinc chloride (II) (1.9mg, 0.014mmol) are in ring
It is stirred 10 minutes at a temperature of border, to provide colourless solution, then adds sodium cyanoborohydride (8.78mg, 0.140mmol), and will
Mixture stirs 1 hour.Solvent is removed under stress, and residue is purified on 10g silicagel column via chromatography,
Ethyl acetate/methanol (10: 1) in heptane is eluted with 0-40%, to obtain ester (2S, 3S, 4S, 5S)-ethyl 3- (tertiary fourth
Base) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2- cyclopropyl pyridine -3- base) -1- ((S)-tetrahydrofuran -
2- carbonyl) pyrrolidines -2- formic acid esters, it is dissolved in methanol (1.5mL) and the aqueous LiOH of 6M (0.5mL).By mixture 50
It is stirred 4 hours at DEG C, pH is adjusted to 4-5, is then concentrated.Residue is dissolved in methylene chloride (1mL) and passes through syringe
The filtering of formula filter.Filtrate is purified on 4g silicagel column via chromatography, with methanol in methylene chloride with 0-20%'s
Gradient elution, to provide title compound, 61mg (76% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm 8.32
(dd, J=4.9,1.6Hz, 1H), 8.22 (d, J=7.9Hz, 1H), 7.18 (td, J=8.3,3.8Hz, 2H), 6.97 (d, J=
2.5Hz, 1H), 6.76 (d, J=8.6Hz, 1H), 5.77 (s, 1H), 4.69 (d, J=1.5Hz, 1H), 3.76 (d, J=7.0Hz,
1H), 3.74-3.62 (m, 4H), 3.53 (s, 3H), 3.31 (d, J=7.3Hz, 1H), 3.07 (q, J=7.3Hz, 1H), 2.53
(s, 1H), 2.12-2.07 (m, 1H), 1.99-1.91 (m, 1H), 1.81-1.71 (m, 2H), 1.22 (d, J=7.3Hz, 1H),
1.19 (s, 9H), 1.09-1.04 (m, 1H), 1.03 (s, 9H), 0.98-0.93 (m, 2H), 0.91-0.81 (m, 2H)；MS(ESI
+)m/z 578.2(M+H)+。
Example 97
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (ethoxy carbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 77B (38mg, 0.073mmol, 1.0 equivalent) and triethylamine (31 μ L, 0.29mmol, 3.0 equivalent) are dissolved in
In methylene chloride (0.5mL).Add pure ethyl chloroformate (11.9mg, 0.11mmol, 1.5 equivalent).Reaction is stirred in room temperature
It mixes 2 hours.Reaction is concentrated, residue is dissolved in 3: 2 tetrahydrofurans/methanol (1mL).Add aqueous LiOH monohydrate
(5M, 300 μ L), and reaction is stirred overnight at 45 DEG C.Solvent is removed under nitrogen flowing.By the residue aqueous HCl of 2M
It is acidified and uses CH3CN dilution.(29.3mg, 59% yield) is purified using preparative reversed-phase HPLC MS method AA7.1HNMR
(400MHz, 120 DEG C, dimethyl sulfoxide-d6∶D2O=9: 1 (v/v)) δ ppm 8.26 (s, 1H), 7.89-7.82 (m, 1H), 7.48
(d, J=2.4Hz, 1H), 7.25-7.13 (m, 2H), 7.11-7.02 (m, 1H), 5.26 (d, J=6.5Hz, 1H), 4.36 (d, J
=1.6Hz, 1H), 3.85 (q, J=7.0Hz, 2H), 3.70 (s, 3H), 3.46 (d, J=15.1Hz, 1H), 3.31 (d, J=
6.5Hz, 1H), 3.20 (d, J=15.1Hz, 1H), 3.08-3.00 (m, 1H), 2.35 (d, J=1.6Hz, 1H), 1.18 (d, J=
6.8Hz, 3H), 1.07 (d, J=6.8Hz, 3H), 0.99 (s, 9H), 0.90 (t, J=7.0Hz, 3H)；MS(APCI+)m/z
566.1(M+H)+。
Example 98
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (Cyclopentanecarbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
It is small 4mL will to be added in the cyclopentane-carboxylic acid (12.5mg, 0.11mmol, 1.5 equivalent) in methylene chloride (500 μ L)
In bottle.Pure Ghosez reagent (1- chloro- N, N, 2- trimethyl -1- allylamine, 20 μ L, 0.14mmol, 2.0 equivalents) are added,
And reaction is stirred at room temperature 10 minutes.Add in 1: 1 tetrahydrofuran/pyridine (500 μ L) example 77B (38mg,
0.072mmol, 1.0 equivalents), and reaction is stirred at room temperature 2 hours.Reaction is concentrated, residue is dissolved in 3: 2 tetrahydro furans
Mutter/methanol (1mL) in.It adds aqueous LiOH monohydrate (5M, 300 μ L), and reaction is stirred overnight at 45 DEG C.By solvent
It removes under nitrogen flowing.The residue aqueous HCl of 2M is acidified, and uses CH3CN dilution.Use the preparative reversed-phase HPLC side MS
Method AA8 is purified (31.9mg, 62% yield).1HNMR (400MHz, 120 DEG C, dimethyl sulfoxide-d6∶D2O=9: 1 (v/v))
δ ppm 8.26 (d, J=2.2Hz, 1H), 7.82 (s, 1H), 7.49 (d, J=2.5Hz, 1H), 7.29-7.17 (m, 2H), 7.09
(t, J=7.3Hz, 1H), 5.40 (d, J=6.6Hz, 1H), 4.56 (s, 1H), 3.70 (s, 3H), 3.50 (d, J=15.0Hz,
1H), 3.38 (d, J=6.5Hz, 1H), 3.23 (d, J=15.0Hz, 1H), 3.12-2.97 (m, 2H), 2.39 (s, 1H), 1.79-
1.23 (m, 8H), 1.18 (t, J=6.7Hz, 3H), 1.06 (d, J=6.8Hz, 3H), 0.99 (s, 9H)；MS(APCI+)m/z
590.1(M+H)+。
Example 99
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
Example 99A
(2S, 3R, 4S, 5S) -2- ethyl 1- isopropyl 5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tertiary fourth
Base) -4- nitro-pyrrole alkane -1,2- dicarboxylic acid esters
Replace core 16 with core 17, title compound is prepared according to program described in example 78A.LC/MS(APCI+)m/z
463.34(M+H)+。
Example 99B
(2S, 3S, 4S, 5S) -2- ethyl 1- isopropyl 4- amino -5- (2- (azetidine -1- base) pyridin-3-yl) -
3- (tert-butyl) pyrrolidines -1,2- dicarboxylic acid esters
Replace example 78A with example 99A, title compound is prepared according to program described in example 78B.LC/MS(APCI
+)m/z 433.44(M+H)+。
Example 99C
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid
By example 99B (44.2mg, 0.10mmol, 1.0 equivalent) and 2- methoxyl group -4- tert-butyl benzene formaldehyde (23.6mg,
0.12,1.2 equivalent) it is dissolved in sodium acetate/acetate buffer (pH=4,1mL) in methyl alcohol.By sodium cyanoborohydride
(12.84mg, 0.24mmol, 2.0 equivalent) is dissolved in methanol and is added in reaction.Reaction is stirred at room temperature 20 minutes.It will
Solvent removes under nitrogen flowing.Residue is dissolved in methylene chloride/H2In O, and water phase is extracted with methylene chloride (2x1mL).
Organic layer is concentrated.Residue is dissolved in 3: 2 tetrahydrofurans/methanol (1mL).Add aqueous LiOH monohydrate (5M, 300 μ
L it), and by reaction is stirred overnight at 45 DEG C.Solvent is removed under nitrogen flowing.Residue is acidified with the aqueous HCl of 2M and is used in combination
CH3CN dilution.(34.7mg, 49% yield) is purified using preparative reversed-phase HPLC MS method trifluoroacetic acid 6.1HNMR
(400MHz, 120 DEG C, dimethyl sulfoxide-d6∶D2O=9: 1 (v/v)) δ ppm 8.04 (d, J=7.5Hz, 1H), 7.99 (d, J=
4.8Hz, 1H), 7.17 (dd, J=8.4,2.5Hz, 1H), 7.01 (d, J=2.5Hz, 1H), 6.76 (d, J=8.5Hz, 1H),
6.67 (dd, J=7.5,4.8Hz, 1H), 4.89 (d, J=6.4Hz, 1H), 4.65-4.54 (m, 1H), 4.31 (s, 1H), 3.90
(q, J=7.4Hz, 2H), 3.81-3.72 (m, 2H), 3.61 (d, J=14.0Hz, 1H), 3.44 (s, 3H), 3.33-3.24 (m,
2H), 2.32 (s, 1H), 2.10 (p, J=7.4Hz, 2H), 1.20 (d, J=0.8Hz, 9H), 1.03 (d, J=6.3Hz, 3H),
0.96 (s, 9H), 0.86 (d, J=6.2Hz, 3H)；MS(APCI+)m/z 581.2(M+H)+。
Example 100
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- [(2S)-oxygen penta
Ring -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 100A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- nitro -1- ((S)-tetrahydrofuran -
2- carbonyl) pyrrolidines -2- formic acid esters
The reflux 1 in thionyl chloride (30mL, 411mmol) by (S)-tetrahydrofuran -2- formic acid (3.64g, 31.3mmol)
Hour.Reaction mixture is cooled to room temperature, and mixture is concentrated in a vacuum.Use CH2Cl2Expel excessive thionyl chloride
Three times, and by thick acid chloride (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- the isopropyl phenyl) -4- nitre of gained
Base pyrrolidines -2- formic acid esters (core 8,5.30g, 14.62mmol) is in CH2Cl2Solution processing in (78mL), and use pyridine
(15.2mL, 188mmol) processing.The reaction is stirred at room temperature.After 2 hours, reaction mixture is diluted with ethyl acetate, and
It is washed with water three times, is washed with brine primary.By organic layer through Na2SO4It dries, filters and is concentrated in a vacuum to provide thick mark
Compound is inscribed, is directly entered it without further purification in next reaction.MS(APCI+)m/z 461.4(M+H)+。
Example 100B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- isopropyl phenyl) -1- ((S)-tetrahydrofuran -
2- carbonyl) pyrrolidines -2- formic acid esters
It will be added in the example 100A (6.202g, 13.47mmol) in tetrahydrofuran (60mL) in 250mL SS pressure resistance
In bottleIn nickel 2800 (aqueous slurry, through solvent washing, 15.4g, 118mmol after weighing), with argon cleaning 3 times,
It is rinsed with hydrogen, and is vibrated under 50psi hydrogen.After 15.7 hours, mixture is filtered by polypropylene screen, and will be muddy
Filtrate is stirred 20 minutes together with magnesium sulfate.Clear solution is filtered by diatomite, and is concentrated in a vacuum to provide mark
Inscribe compound, 525g (91%).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.90 (d, J=7.8Hz, 1H), 7.30 (m
1H), 7.21 (m, 1H), 7.13 (m, 1H), 5.57 (m, 1H), 4.56-4.50 (m, 1H), 4.17 (q, J=7.1Hz, 2H), 4.07
(m, 1H), 3.64 (m, 2H), 3.20 (m, 1H), 2.06 (m, 1H), 1.94 (m, 1H), 1.62 (m, 1H), 1.47 (m, 2H),
1.31-1.19 (m, 9H), 1.00 (s, 9H)；MS(ESI+)m/z 431.3(M+H)+。
Example 100C
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- isopropyl phenyl) -4- (((2 methoxy quinoline -3- base)
Methyl) amino) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
It will be in the example 100B (0.150g, 0.348mmol) and 2 methoxy quinoline -3- first in dichloroethanes (1.7mL)
Aldehyde (0.065g, 0.348mmol) is handled with sodium triacetoxy borohydride (0.103g, 0.488mmol), and will be reacted in room temperature
Lower stirring.After 30 minutes, reaction mixture 1.7mL is saturated NaHCO3Aqueous solution processing, and be vigorously stirred 30 minutes.By this
It is a little mutually to separate, and by water layer CH2Cl2Extraction is three times.By combined organic matter through Na2SO4It dries, filters and is being concentrated in vacuo,
And be purified by silica gel chromatography thick residue, the elution of 0 to 20% ethyl acetate-heptane of use, to obtain title compound,
0.169g (81% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.94 (d, J=7.9Hz, 1H), 7.69-7.59
(m, 3H), 7.53 (ddd, J=8.3,7.0,1.4Hz, 1H), 7.38-7.20 (m, 3H), 7.14 (t, J=7.4Hz, 1H), 5.64
(m, 1H), 4.73 (m, 1H), 412 (m, 3H), 3.73 (s, 3H), 3.71-3.53 (m, 3H), 3.45 (m, 1H), 3.35 (m, 1H),
3.09 (m, 1H), 2.42 (m, 1H), 2.04-1.93 (m, 1H), 1.79 (dq, J=14.0,6.9Hz, 1H), 1.64 (m, 2H),
1.23-1.13 (m, 6H), 1.03 (s, 9H), 1.09-0.98 (m, 3H)；MS(ESI+)m/z 602.4(M+H)+。
Example 100D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- [(2S)-oxygen penta
Ring -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
By example 100C (0.169g, 0.281mmol) and lithium hydroxide (1M is aqueous) (2.8mL, 2.80mmol) in tetrahydro
It is stirred overnight at 45 DEG C in furans (2.8mL) and methanol (2.8mL).After this, reaction mixture is cooled to room temperature and is used in combination
The aqueous HCl of 1N is acidified to pH 2.Mixture is diluted with 5mL water and uses CH2Cl2Extraction is three times.Combined organic matter is passed through
Na2SO4It dries, filters and is being concentrated in vacuo, and gained residue is purified by silica gel chromatography, 0 to 2% methanol-acetic acid of use
Ethyl ester elution, to obtain title compound, 0.097g (60% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm
7.94 (d, J=7.8Hz, 1H), 7.65 (m, 3H), 7.54 (t, J=7.7Hz, 1H), 7.38-7.20 (m, 3H), 7.12 (m,
1H), 5.62 (m, 1H), 4.62 (m, 1H), 4.11 (m, 1H), 3.74 (s, 3H), 3.69 (d, J=7.1Hz, 1H), 3.59 (m,
2H), 3.44 (d, J=6.7Hz, 1H), 3.35 (d, J=14.8Hz, 1H), 3.07 (m, 1H), 2.44 (m, 1H), 1.95 (m,
1H), 1.84-1.75 (m, 1H), 1.64 (m, 2H), 1.18 (d, J=6.9Hz, 3H), 1.02 (m, 12H)；MS(ESI+)m/z
574.3(M+H)+。
Example 101
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 101A
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((5- cyclopropyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- cyclopropyl phenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
By example 95B (116.3mg, 0.270mmol) and 5- cyclopropyl -2- methoxyl group cigarette aldehyde (47.9mg, 0.270mmol)
It is dissolved in dichloroethanes (4mL).It adds sodium triacetoxy borohydride (78.1mg, 0.368mmol), and will react in environment temperature
Degree lower stirring 1 hour.Reaction is diluted with methylene chloride (35mL), and is quenched with saturation aqueous sodium bicarbonate (35mL), and stir
It mixes 30 minutes.Organic layer is separated, and water layer is extracted with methylene chloride (35mL).By combined organic layer through Na2SO4It is dry,
It filters and is concentrated.Residue is purified by silica gel chromatography (10% ethyl acetate in methylene chloride), to provide title
Compound (70.1mg, 44%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.89 (d, J=7.8Hz, 1H),
7.73 (d, J=2.4Hz, 1H), 7.25 (dd, J=15.8,7.4Hz, 2H), 7.11 (t, J=7.5Hz, 1H), 6.86 (d, J=
2.4Hz, 1H), 5.69-5.55 (m, 2H), 4.71 (s, 1H), 4.11 (qd, J=7.0,0.9Hz, 2H), 3.67 (q, J=
7.2Hz, 1H), 3.62-3.51 (m, 5H), 3.40 (dd, J=14.0,6.4Hz, 3H), 3.13 (ddd, J=33.9,13.9,
6.5Hz, 2H), 2.37 (s, 1H), 2.05-1.91 (m, 1H), 1.84-1.55 (m, 3H), 1.25-1.14 (m, 6H), 1.07 (dd,
J=6.8,1.2Hz, 3H), 1.02 (d, J=0.9Hz, 9H), 0.88-0.79 (m, 2H), 0.50-0.41 (m, 2H)；MS(ESI+)
m/z 592(M+H)+。
Example 101B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 101A (67.0mg, 0.113mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in double trifluoroacetates
Title compound (73.4mg, 82%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.86 (d, J=
7.8Hz, 1H), 7.76 (d, J=2.4Hz, 1H), 7.30 (dd, J=7.8,1.5Hz, 1H), 7.25 (t, J=7.4Hz, 1H),
7.14 (t, J=7.6Hz, 1H), 6.94 (d, J=2.4Hz, 1H), 5.65 (s, 1H), 4.65 (d, J=1.5Hz, 1H), 4.12
(s, 1H), 3.68 (q, J=7.2Hz, 1H), 3.59 (s, 3H), 3.57-3.49 (m, 4H), 3.19 (d, J=14.1Hz, 1H),
3.10 (h, J=6.8Hz, 1H), 2.45 (s, 1H), 2.04-1.92 (m, 1H), 1.84-1.56 (m, 3H), 1.22 (d, J=
6.7Hz, 3H), 1.09 (d, J=6.8Hz, 3H), 1.02 (s, 8H), 0.88-0.80 (m, 2H), 0.53-0.43 (m, 2H)；MS
(ESI+)m/z 564(M+H)+。
Example 102
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -1- (cyclobutanecarbonyl) pyrrolidines -2- formic acid
Example 102A
(2S, 3R, 4S, 5S)-ethyl 5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tert-butyl) -1- (ring fourth
Alkyl carbonyl) -4- nitro-pyrrole alkane -2- formic acid esters
To the cyclobutane formate (50.0mg, 0.5mmol) and a drop n,N-Dimethylformamide in methylene chloride (5mL)
Middle addition oxalyl dichloro (127mg, 1.0mmol, 0.5mL, 2M are in methylene chloride).Mixture is stirred 30 points in environment temperature
Clock.Solvent is removed under stress, and adds fresh methylene chloride (5mL) and then removes again.Residue is dissolved in dichloromethane
In alkane (1mL), and it is added dropwise to (2S, 3R, 4S, 5S)-ethyl 5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tertiary fourth
Base) -4- nitro-pyrrole alkane -2- formic acid esters (core 17,94mg, 0.250mmol) and triethylamine (0.139mL, 0.999mmol) be in ice
In solution in bath in cooling methylene chloride (6mL).Mixture is stirred 30 minutes in ice bath and it is made to be warmed to environment
Temperature.Add methylene chloride (10mL) and the aqueous NH of saturation4Cl (10mL), and organic layer is washed with brine, through MgSO4It is dry,
It filters and dries.Residue is purified on 12g silicagel column via chromatography, the ethyl acetate in heptane is with 0-40%'s
Gradient elution, to obtain (2S, 3R, 4S, 5S)-ethyl 5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tert-butyl) -
1- (cyclobutanecarbonyl) -4- nitro-pyrrole alkane -2- formic acid esters 110mg (96% yield).LC/MS(APCI+)m/z 459.32(M+
H)+。
Example 102B
(2S, 3S, 4S, 5S)-ethyl 4- amino -5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tert-butyl) -
1- (cyclobutanecarbonyl) pyrrolidines -2- formic acid esters
Replace example 10B with example 102A, title compound is prepared according to program described in example 10C.LC/MS
(APCI+)m/z 429.37(M+H)+。
Example 102C
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -1- (cyclobutanecarbonyl) pyrrolidines -2- formic acid
By 5- (tert-butyl)-Benzaldehyde,2-methoxy in sodium acetate/acetate buffer (pH=4,2mL) in methanol
(24.67mg, 0.128mmol), (2S, 3S, 4S, 5S)-ethyl 4- amino -5- (2- (azetidine -1- base) pyridine -3-
Base) -3- (tert-butyl) -1- (cyclobutanecarbonyl) pyrrolidines -2- formic acid esters (example 102B, 50mg, 0.117mmol) and zinc chloride
(II) (15.90mg, 0.117mmol) is stirred at room temperature 10 minutes, to provide colourless solution.Add pure sodium cyanoborohydride
(11.00mg, 0.175mmol), and mixture is stirred at room temperature 1 hour.By solvent in N2Lower removal.Residue is passed through
Chromatography purifying, the ethyl acetate/methanol (10: 1) in heptane elutes with 0-40%, has more polarity in the form of obtaining than S-
Ester.The ester is dissolved in methanol (2mL) and the aqueous LiOH of 4M (0.5mL).Mixture is stirred 4 hours at 40 DEG C.It will be molten
Agent removal, is added water (1mL), and pH is adjusted to 4-5.The purifying carried out by chromatography (is used in CH2Cl2In methanol with 0-
20% elution) (2S, 3S, 4S, 5S) -5- (2- (azetidine -1- base) pyridin-3-yl) -3- (tert-butyl) -4- ((5- is provided
(tert-butyl) -2- methoxy-benzyl) amino) -1- (cyclobutanecarbonyl) pyrrolidines -2- formic acid (18mg, 0.031mmol, 26.7%
Yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.03 (dd, J=4.8,1.7Hz, 1H), 7.22-7.12 (m,
1H), 7.01 (dd, J=19.8,2.6Hz, 1H), 6.77 (d, J=8.5Hz, 2H), 6.74-6.63 (m, 1H), 4.96 (d, J=
6.4Hz, 1H), 4.45 (s, 1H), 4.25 (s, 2H), 3.95 (q, J=7.5Hz, 2H), 3.79-3.69 (m, 2H), 3.64 (s,
1H), 3.44 (s, 3H), 3.38-3.28 (m, 2H), 2.39 (s, 1H), 2.10 (td, J=13.5,12.4,6.1Hz, 4H), 2.00
(s, 2H), 1.73 (s, 2H), 1.21 (d, J=2.5Hz, 9H), 0.96 (d, J=8.5Hz, 9H)；MS(ESI+)m/z 577.4(M
+H)+。
Example 103
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- chlorphenyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 103A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters
By (2- (bis- (3,5- bis- (trifluoromethyl) phenyl) phosphino-s) -3- ((S) -4- isopropyl -4,5- dihydro-oxazole -2-
Base) amyl- 2, the 4- diene -1- base of ring) (amyl- 2, the 4- diene -1- base of ring) iron (0.175g, 0.232mmol) and copper trifluoromethanesulfcomposite
(II) (0.047g, 0.093mmol) is dissolved in the tetrahydrofuran (19.36mL) for spraying 1 hour with nitrogen stream.Gained is mixed
It closes object to stir at ambient temperature 1 hour (continuing nitrogen jet), and adds (E)-ethyl 2- ((2- chlorine benzal) amino) second
Solution of the acid esters (2.75g, 12.19mmol) in 2mL tetrahydrofuran, and acquired solution is cooled to 5 DEG C of < in ice-water bath.
The 2- methyl propyl- 2- potassium alcoholate (0.209mL, 0.209mmol) in tetrahydrofuran is added dropwise, then through addition pure (E)-in 20 minutes
3,3- dimethyl -1- nitro but-1-enes (1.5g, 11.61mmol) keep temperature to be lower than 7 DEG C.Reaction mixture is stirred at 0 DEG C
It mixes 1 hour.Mixture 60mL is saturated aqueous ammonium chloride and 100mL ethyl acetate quenches, and is warmed to environment temperature.To have
The separation of machine layer is washed twice with aqueous ammonium chloride washed is saturated, is then washed with brine, and filtered by silicagel pad.Organic matter is dense
Contracting.It adds heptane (70mL), and mixture is filtered to provide sediment (2.5g).By filtrate by using 12g silicagel column
Chromatography is purified, with 0-60% heptane/ethyl acetate gradient elution 20 minutes, with offer (2S, 3R, 4S, 5S)-ethyl
3- (tert-butyl) -5- (2- chlorphenyl) -4- nitro-pyrrole alkane -2- formic acid esters (285g, 803mmol, 69.2% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.56-748 (m, 1H), 7.45-7.38 (m, 1H), 7.35-7.24 (m, 2H),
5.25 (dd, J=6.7,3.0Hz, 1H), 4.71 (t, J=7.0Hz, 1H), 4.19 (qq, J=7.3,3.7Hz, 2H), 3.78 (t,
J=7.3Hz, 1H), 3.68 (t, J=7.3Hz, 1H), 3.07 (dd, J=7.4,3.0Hz, 1H), 1.24 (t, J=7.1Hz,
3H), 0.94 (s, 9H), 0.96 (s, 9H)；MS(APCI+)m/z 355(M+H)+。
Example 103B
(2S, 3R, 4S, 5S) -1- allyl 2- ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- nitro-pyrrole alkane -1,2-
Dicarboxylic acid esters
At ambient temperature, in toluene (9.34mL) and the aqueous NaHCO of saturation3Example 103A in (9.34mL)
Allyl chlorocarbonate (0.880mL, 8.03mmol) is added dropwise in (2.85g, 8.03mmol).Mixture is stirred at ambient temperature
Overnight.Methylene chloride (60mL) and water (30mL) are added, and organic layer is washed with brine and is concentrated.By rough material with 50mL heptan
Alkane grinding, is filtered to provide sediment (2.03g).Filtrate is purified on 12g column, with 0-80% ethyl acetate/heptane
Gradient elution 12 minutes, with offer (2S, 3R, 4S, 5S) -1- allyl 2- ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4-
Nitro-pyrrole alkane -1,2- dicarboxylic acid esters (3.52g, 8.02mmol, 100% yield).1H NMR (400MHz, dimethyl sulfoxide-d6)
δ ppm 7.90 (s, 1H), 7.44-7.36 (m, 1H), 7.36-7.24 (m, 2H), 5.82 (bs, 1H), 5.68 (s, 1H), 5.60-
5.52 (m, 1H), 5.05 (d, J=91.9Hz, 2H), 4.59 (d, J=3.3Hz, 1H), 4.46 (bs, 2H), 4.24 (q, J=
7.1Hz, 2H), 3.05 (t, J=3.0Hz, 1H), 1.26 (t, J=7.1Hz, 3H), 1.00 (s, 9H)；MS(APCI+)m/z 439
(M+H)+。
Example 103C
(2S, 3S, 4S, 5S) -1- allyl 2- ethyl 4- amino -3- (tert-butyl) -5- (2- chlorphenyl) pyrrolidines -1,2-
Dicarboxylic acid esters
Example 103B (240mg, 0.547mmol) is dissolved in tetrahydrofuran (2734 μ L), and add zinc (358mg,
5.47mmol), then acetic acid (203 μ l, 3.55mmol) is added.Reaction is stirred overnight at 40 DEG C.It adds acetic acid (50 μ L),
And mixture is stirred at ambient temperature two hours.Mixture is filtered, and filtrate is concentrated.Thick residue is used
The gradient of 5%-100% ethyl acetate/heptane is purified, to provide (2S, 3S, 4S, 5S) -1- allyl 2- ethyl 4- ammonia
Base -3- (tert-butyl) -5- (2- chlorphenyl) pyrrolidines -1,2- dicarboxylic acid esters (175mg, 0.428mmol, 78% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.89 (dd, J=7.7,1.9Hz, 1H), 7.36 (dd, J=7.7,1.5Hz, 1H),
7.32-7.18 (m, 2H), 5.77-5.63 (m, 1H), 5.26 (d, J=6.8Hz, 1H), 5.04 (d, J=1.6Hz, 1H), 5.03-
4.97 (m, 1H), 4.42-4.37 (m, 3H), 4.19 (q, J=7.0Hz, 2H), 3.81 (dd, J=6.8,2.3Hz, 1H), 2.09
(t, J=2.7Hz, 1H), 1.25 (t, J=7.1Hz, 3H), 1.00 (s, 9H), 0.87-0.74 (m, 2H)；MS(ESI+)m/z
409(M+H)+。
Example 103D
(2S, 3S, 4S, 5S) -1- allyl 2- ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- (((5- cyclobutyl -2-
Methoxypyridine -3- base) methyl) amino) pyrrolidines -1,2- dicarboxylic acid esters
By example 103C (95mg, 0.232mmol), zinc chloride (II) (41mg, 0.301mmol) and 5- cyclobutyl -2- first
Oxygroup cigarette aldehyde (59mg, 0.309mmol) is dissolved in sodium acetate/acetate buffer (pH=4,669 μ L) in methyl alcohol.It will mixing
Object stirs 25 minutes in environment temperature.It adds three sodium borohydride of cyano (24mg, 0.382mmol), and will react in environment temperature
Lower stirring 90 minutes.Solvent is removed under a nitrogen.Residue is diluted with aqueous sodium bicarbonate, and rough material is absorbed in two
In chloromethanes, and purified using ethyl acetate/heptane solvent system with 10g silicagel column, to obtain (2S, 3S, 4S, 5S)-
1- allyl 2- ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) pyrrolidines -1,2- dicarboxylic acid esters (89mg, 0.152mmol, 65.6% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δ
Ppm 7.91 (dd, J=7.1,2.4Hz, 1H), 7.77 (d, J=2.4Hz, 1H), 7.35 (dd, J=7.1,2.1Hz, 1H),
7.30-7.18 (m, 2H), 7.12 (d, J=2.4Hz, 1H), 5.70 (ddt, J=17.7,10.2,5.1Hz, 1H), 5.32 (d, J
=6.5Hz, 1H), 5.04 (s, 1H), 5.03-4.97 (m, 1H), 4.48 (d, J=1.6Hz, 1H), 4.43-4.37 (m, 2H),
4.14 (q, J=7.1Hz, 2H), 3.64 (s, 3H), 3.56 (dd, J=6.7,2.9Hz, 1H), 3.47-3.34 (m, 2H), 3.26
(dd, J=14.3,6.7Hz, 1H), 2.37 (s, 1H), 2.26 (tdt, J=6.7,4.5,2.0Hz, 2H), 2.05-1.90 (m,
3H), 1.85 (tt, J=7.4,3.4Hz, 1H), 1.19 (t, J=7.2Hz, 3H), 0.99 (s, 9H)；MS(ESI+)m/z 584(M
+H)+。
Example 103E
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- (((5- cyclobutyl -2- methoxypyridine -
3- yl) methyl) amino) pyrrolidines -2- formic acid esters
Example 103D (89mg, 0.152mmol) is dissolved in nitrogen stream by being bubbled the ethyl acetate (5mL) being de-gassed
In methylene chloride (5mL), and with 1,3- dimethyl pyrimidine -2,4,6 (1H, 3H, 5H)-triketones (47.6mg, 0.305mmol) and
Tetrakis triphenylphosphine palladium (0) (1.1mg, 0.914 μm of ol) processing.Reaction is stirred at ambient temperature.After ten minutes, it will react
Mixture is saturated aqueous NaHCO with 2mL3Quenching, and pass through aqueous/organic separating pipe.Solvent is removed, and thick organic matter is made
Purifying 20 minutes is carried out with 12g silicagel column with the gradient of 5%-100% ethyl acetate/heptane, to provide (2S, 3S, 4S, 5S)-
Ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) amino) pyrrolidines -
2- formic acid esters (71mg, 0.142mmol, 93% yield).1HNMR (400MHz, chloroform-d) δ ppm 7.80-7.76 (m, 1H),
7.69 (dd, J=7.6,1.8Hz, 1H), 7.39 (dd, J=7.8,1.5Hz, 1H), 7.32 (td, J=7.5,1.5Hz, 1H),
7.28-7.23 (m, 1H), 7.08 (d, J=2.4Hz, 1H), 4.45 (d, J=4.4Hz, 1H), 4.25 (qd, J=7.1,2.2Hz,
2H), 3.76 (s, 3H), 3.69 (d, J=6.1Hz, 1H), 3.42 (d, J=8.9Hz, 1H), 3.38 (dd, J=4.5,1.3Hz,
1H), 3.22 (s, 2H), 2.35-2.19 (m, 2H), 2.11 (dd, J=6.1,1.3Hz, 1H), 2.08-1.96 (m, 3H), 1.87
(dtt, J=4.8,3.9,2.3Hz, 1H), 1.31 (t, J=7.1Hz, 3H), 0.97 (s, 9H)；(APCI+)m/z 500(M+H)+。
Example 103F
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- (((5- cyclobutyl -2- methoxypyridine -
3- yl) methyl) amino) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
Example 103E (70mg, 0.140mmol) is dissolved in ice bath in cooling methylene chloride (1mL), and with three second
Amine (0.078mL, 0.560mmol) and (S)-tetrahydrofuran -2- phosgene (37.7mg, 0.280mmol) are in 1mL methylene chloride
In solution processing.Reaction is stirred 20 minutes at ambient temperature.Reaction mixture 2mL is saturated aqueous NaHCO3It is sudden
It goes out, these is mutually separated, and organic matter is concentrated.Thick organic matter is used into 12g silicagel column 5%-60% ethyl acetate/heptane
Gradient carry out purifying 20 minutes, to provide 68mg crude product, and by mixture further use trifluoroacetic acid method use it is anti-
Phase HPLC is purified, to provide (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- chlorphenyl) -4- (((5- cyclobutyl -
2- methoxypyridine -3- base) methyl) amino) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters (45mg,
0.075mmol, 53.7% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.93 (s, 1H), 7.77 (d, J=
2.4Hz, 1H), 7.38 (dd, J=6.1,3.0Hz, 1H), 7.27 (dt, J=5.9,2.8Hz, 2H), 7.14 (d, J=2.4Hz,
1H), 5.59 (s, 1H), 4.73 (s, 1H), 4.14 (q, J=7.1Hz, 2H), 3.67 (d, J=8.5Hz, 4H), 3.59 (d, J=
7.1Hz, 1H), 3.47 (d, J=14.2Hz, 1H), 3.43-3.35 (m, 1H), 3.27 (d, J=14.3Hz, 1H), 2.37 (s,
1H), 2.26 (dddd, J=13.3,7.0,3.9,1.8Hz, 2H), 2.05-1.92 (m, 6H), 1.87-1.61 (m, 4H), 1.20
(t, J=7.1Hz, 3H), 0.98 (d, J=2.1Hz, 9H).
Example 103G
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- chlorphenyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 103F (45mg, 0.075mmol) is dissolved in methanol (1mL) and tetrahydrofuran (1.0mL), and uses hydroxide
Solution processing of the lithium (18.02mg, 0.752mmol) in water (0.5mL).Reaction is warmed 3 hours in 45 DEG C of heat block.
Reaction is concentrated, then reaches pH 6 using the aqueous HCl of 2N (300 μ L).Thick organic matter is used into 10g silicagel column acetic acid
Ethyl ester/ethyl alcohol/heptane solvent system is purified, to provide (2S, 3S, 4S, 5S) -3- (tert-butyl) -5- (2- chlorphenyl) -4-
(((5- cyclobutyl -2- methoxypyridine -3- base) methyl) amino) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid
(41mg, 0.072mmol, 96% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.04 (s, 1H), 7.76 (d, J
=2.4Hz, 1H), 7.35 (d, J=7.0Hz, 1H), 7.29-716 (m, 2H), 7.12 (d, J=2.4Hz, 1H), 5.55 (s,
1H), 4.55 (s, 1H), 3.78-3.68 (m, 1H), 3.68 (s, 3H), 3.69-3.57 (m, 1H), 3.52 (d, J=7.1Hz,
1H), 3.46 (d, J=14.8Hz, 1H), 3.41-3.34 (m, 1H), 3.25 (d, J=14.8Hz, 1H), 2.67-2.60 (m,
1H), 2.38 (s, 1H), 2.26 (dddt, J=13.1,8.5,5.4,2.7Hz, 2H), 2.04-1.87 (m, 5H), 1.89-1.76
(m, 2H), 1.70 (s, 1H), 0.96 (s, 9H)；(APCI+)m/z 570(M+H)+。
Example 104
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 104A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- (2-
Isopropyl phenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
By example 100B (0.150g, 0.348mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (0.067g,
0.348mmol) in the solution in dichloroethanes (1.7mL) at sodium triacetoxy borohydride (0.103g, 0.488mmol)
Reason, and reaction is stirred at room temperature.After 30 minutes, reaction mixture 1.7mL is saturated NaHCO3Aqueous solution processing, and it is acute
Strong stirring 30 minutes.These are mutually separated, and by water layer CH2Cl2Extraction is three times.By combined organic matter through Na2SO4It is dry,
It filters and is concentrated in a vacuum, and rough material is purified by silica gel chromatography, 0 to 30% ethyl acetate-heptane of use elution 15
Minute, to obtain title compound, 0.180g (85% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.89 (d,
J=7.7Hz, 1H), 7.23 (m, 2H), 7.08 (m, 2H), 6.88 (d, J=2.6Hz, 1H), 6.66 (d, J=8.5Hz, 1H),
5.62 (m, 1H), 4.72 (m, 1H), 4.10 (m, 3H), 3.67 (m, 2H), 3.51 (m, 1H), 3.41 (m, 4H), 3.18 (m, 1H),
3.07 (m, 1H), 2.41 (m, 1H), 1.97 (m, 1H), 1.78-1.63 (m, 3H), 1.23-1.13 (m, 15H), 1.03 (m,
12H)；MS(ESI+)m/z 607.4(M+H)+。
Example 104B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
By example 104A (0.180g, 0.297mmol) and lithium hydroxide (1M is aqueous) (3mL, 3.00mmol) in tetrahydro furan
Mutter (3mL) and methanol (3mL) in be stirred overnight at 45 DEG C.After this, mixture is acidified to pH 2 with the aqueous HCl of 1N, and
It is concentrated in a vacuum.By being existed by excessive moisture removal, and by rough material by reversed-phase HPLC with acetonitrile azeotropicC8(2)5umIt is purified on AXIA column (30mm × 75mm).Using acetonitrile (A) and in water
0.1% trifluoroacetic acid (B) gradient, flow velocity be 50mL/ minutes (0-1.0 minutes 5%A, 1.0-8.5 minutes linear gradients
5%-100%A, 8.5-11.5 minutes 100%A, 11.5-12.0 minutes linear gradient 95%-5%A), to obtain title compound
Object, 0.066g (38% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.82 (d, J=7.8Hz, 1H), 7.35-
7.13 (m, 4H), 6.98 (d, J=2.6Hz, 1H), 6.75 (d, J=8.5Hz, 1H), 5.67 (m, 1H), 4.64 (d, J=
1.4Hz, 1H), 4.16 (m, 1H), 3.76 (d, J=13.5Hz, 1H), 3.67 (m, 3H), 3.50 (s, 3H), 3.34 (m, 1H),
3.24 (d, J=13.4Hz, 1H), 2.53 (d, J=18.3Hz, 1H), 1.98 (m, 1H), 1.77 (dt, J=14.2,6.8Hz,
1H), 1.66 (m, 2H), 1.22 (d, J=6.8Hz, 3H), 1.19 (s, 9H), 1.12-1.02 (m, 3H), 1.04 (s, 9H)；MS
(ESI+)m/z 579.4(M+H)+。
Example 105
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxypyridine -3-
Base) methyl] amino } -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid
Example 105A
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- (((5- cyclopropyl -2- methoxyl group pyrrole
Pyridine -3- base) methyl) amino) -5- (o-tolyl) pyrrolidines -2- formic acid esters
By example 88B (101.3mg, 0.244mmol) and 5- cyclopropyl -2- methoxyl group cigarette aldehyde (67.2mg, 0.379mmol)
It is dissolved in methanol (1mL).It adds sodium cyanoborohydride (69.9mg, 1.112mmol), and reaction is stirred at ambient temperature
17 hours.Reaction is diluted with methylene chloride (35mL), and is quenched with saturation aqueous sodium bicarbonate (35mL), and stir 30 points
Clock.Organic layer is concentrated and extracts water layer with methylene chloride (2x35mL).By combined organic layer through Na2SO4It dries, filters
And it is concentrated.Residue is purified using ammonium acetate method by reverse phase, to provide title compound (59.4mg, 42%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.85 (s, 1H), 7.75 (d, J=2.4Hz, 1H), 7.15 (s,
3H), 6.87 (d, J=2.4Hz, 1H), 5.24 (d, J=6.6Hz, 1H), 4.60 (s, 1H), 4.19-4.06 (m, 2H), 3.60
(d, J=1.0Hz, 3H), 3.49-3.33 (m, 2H), 3.27-3.17 (m, 1H), 2.35 (s, 1H), 2.19 (s, 3H), 2.10-
1.93 (m, 1H), 1.76 (tt, J=8.4,5.1Hz, 1H), 1.64 (d, J=11.0Hz, 2H), 1.48 (s, 2H), 1.19 (t, J
=7.1Hz, 5H), 0.99 (s, 13H), 0.89-0.79 (m, 2H), 0.52-0.43 (m, 2H).；MS(ESI+)m/z 592(M+H)+。
Example 105B
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxypyridine -3-
Base) methyl] amino } -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid
Example 105A (56.4mg, 0.098mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in double trifluoroacetates
Title compound (48.2mg, 63%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 781 (d, J=
2.4Hz, 1H), 7.75 (s, 1H), 7.18 (d, J=2.8Hz, 3H), 6.99 (d, J=2.4Hz, 1H), 5.30 (d, J=6.8Hz,
1H), 4.56 (d, J=1.6Hz, 1H), 3.69-3.56 (m, 5H), 3.30 (d, J=14.1Hz, 1H), 2.47 (s, 1H), 2.25
(s, 3H), 2.21-2.04 (m, 1H), 1.79 (tt, J=8.4,5.2Hz, 1H), 1.71-1.42 (m, 4H), 1.00 (s, 15H),
0.92-0.81 (m, 2H), 0.57-0.45 (m, 2H)；MS(ESI+)m/z 548(M+H)+。
Example 106
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 106A
Ethyl (2S, 3R, 4S, 5S) -5- (2- bromophenyl) -3- (tert-butyl) -4- nitro -1- ((S)-tetrahydrofuran -2- carbonyl
Base) pyrrolidines -2- formic acid esters
(S)-tetrahydrofuran -2- formic acid (428.8mg, 3.69mmol) is dissolved in methylene chloride (10mL).Add oxalyl
Chlorine (1.8mL, 2M, 3.60mmol) then adds n,N-Dimethylformamide (25 μ L).Reaction is stirred 3 at ambient temperature
Hour, it is concentrated at this time, is re-dissolved in methylene chloride (2mL) and is concentrated again.Residue is absorbed in methylene chloride
In (3x2mL), and core 25 (1.38g, 3.46mmol) and triethylamine (1.5mL, 10.76mmol) are added in methylene chloride
In solution in (10mL).Reaction is stirred 17 hours at ambient temperature.After this, by mixture CH2Cl2(100mL) is dilute
It releases, and with being saturated aqueous NaHCO3It washes twice, and is washed with brine primary.By organic layer through Na2SO4It is dried, filtered and concentrated
To provide title compound (1.58g, 92%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.94 (d, J=
7.8Hz, 1H), 7.59-7.50 (m, 1H), 7.31 (td, J=7.7,3.6Hz, 1H), 7.24-7.14 (m, 1H), 6.02 (s,
1H), 5.57-5.48 (m, 1H), 4.90 (s, 1H), 4.30-4.22 (m, 2H), 3.70 (dq, J=11.4,6.8,6.3Hz, 2H),
3.46 (s, 1H), 3.03 (t, J=2.5Hz, 1H), 2.04-1.89 (m, 1H), 1.78 (ddd, J=23.2,14.8,8.4Hz,
3H), 1.29 (td, J=7.1,0.9Hz, 3H), 1.03 (d, J=1.0Hz, 9H)；MS(ESI+)m/z 497&499(M+H)+。
Example 106B
Ethyl (2S, 3S, 4S, 5S) -4- amino -5- (2- bromophenyl) -3- (tert-butyl) -1- ((S)-tetrahydrofuran -2- carbonyl
Base) pyrrolidines -2- formic acid esters
Example 106A (300mg, 0.603mmol) is dissolved in tetrahydrofuran (3mL), and add zinc (394mg,
6.03mmol), then acetic acid (0.224mL, 3.92mmol) is added.Reaction is heated to 65 DEG C and continues 2 hours.Reaction is filtered
And be concentrated, it is then purified using the gradient of 50%-100% ethyl acetate in methylene chloride, to provide title compound
Object (105.9mg, 0.227mmol, 37.6% yield).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.93 (s,
1H), 7.56 (d, J=7.9Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.17 (t, J=7.6Hz, 1H), 5.50 (s, 1H),
4.60 (s, 1H), 4.18 (q, J=7.1Hz, 2H), 3.85 (dd, J=6.7,2.1Hz, 1H), 3.67 (dd, J=13.4,
6.5Hz, 3H), 2.07 (t, J=2.5Hz, 1H), 2.01-1.90 (m, 1H), 1.85-1.57 (m, 3H), 1.25 (t, J=
7.1Hz, 3H), 1.00 (s, 9H)；MS(ESI+)m/z 467&469(M+H)+。
Example 106C
Ethyl (2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -
3- yl) methyl) amino) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
By example 106B (89.0mg, 0.190mmol) and 5- cyclobutyl -2- methoxyl group cigarette aldehyde (60.0mg, 0.314mmol)
It is dissolved in dichloroethanes (3mL).It adds sodium triacetoxy borohydride (83.8mg, 0.395mmol), and will react in environment temperature
Degree lower stirring 1 hour.Reaction is diluted with methylene chloride (35mL), and is quenched with saturation aqueous sodium bicarbonate (35mL), and stir
It mixes 30 minutes.Organic layer is concentrated and extracts water layer with methylene chloride (2x35mL).By combined organic layer through Na2SO4It is dry
It is dry, it filters and is concentrated.Residue is purified by silica gel chromatography (10% to 20% ethyl acetate in methylene chloride), with
It provides title compound (120.3mg, 98%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 796 (s, 1H),
7.87 (d, J=2.4Hz, 1H), 7.80 (d, J=2.4Hz, 1H), 7.63 (d, J=2.4Hz, 1H), 7.58 (d, J=8.0Hz,
1H), 7.35 (s, 1H), 7.27-7.12 (m, 2H), 5.73-5.33 (m, 1H), 4.77 (s, 1H), 4.63 (dd, J=5.8,
3.6Hz, 1H), 4.25-4.10 (m, 2H), 3.88 (d, J=1.5Hz, 3H), 3.77-3.60 (m, 6H), 3.58-3.36 (m,
3H), 3.29 (dd, J=14.3,7.5Hz, 1H), 2.41-2.23 (m, 4H), 2.17-1.65 (m, 10H), 1.27-1.19 (m,
3H), 1.02 (d, J=1.6Hz, 9H)；MS(ESI+)m/z 642&644(M+H)+。
Example 106D
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base)
Methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 106C (120.3mg, 0.187mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 1.0mL,
1.0mmol) and reaction is heated to 50 DEG C and continues 16 hours.By reaction by the addition aqueous HCl of 1M (1mL) quenching, diformazan is used
Base sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in double trifluoroacetates
Title compound (85.9mg, 55%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.93 (d, J=7.6Hz,
1H), 7.79 (d, J=2.4Hz, 1H), 7.56 (dd, J=7.9,1.3Hz, 1H), 7.33 (t, J=7.5Hz, 1H), 7.23-
7.15 (m, 2H), 5.56 (s, 1H), 4.67 (d, J=1.6Hz, 1H), 4.17 (s, 1H), 3.73-3.61 (m, 6H), 3.52 (d, J
=14.4Hz, 1H), 3.45-3.34 (m, 1H), 3.28 (d, J=14.4Hz, 1H), 2.41 (s, 1H), 2.33-2.18 (m, 2H),
2.05-1.62 (m, 8H), 0.98 (s, 9H)；MS(ESI+)m/z 614&616(M+H)+。
Example 107
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 107A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- nitro -1- ((S)-tetrahydrofuran -
2- carbonyl) pyrrolidines -2- formic acid esters
(S)-tetrahydrofuran -2- formic acid (408.2mg, 3.03mmol) is dissolved in methylene chloride (10mL).Add oxalyl
Chlorine (1.5mL, 2M, 3.00mmol) then adds n,N-Dimethylformamide (25 μ L).Reaction is stirred 3 at ambient temperature
Hour, it is concentrated at this time, is re-dissolved in methylene chloride (2mL) and is concentrated again.Residue is absorbed in methylene chloride
In (3x2mL), and core 14 (905.0mg, 2.51mmol) and triethylamine (1.0mL, 7.17mmol) are added in methylene chloride
In solution in (10mL).Reaction is stirred 17 hours at ambient temperature.After this, by mixture CH2Cl2(100mL) is dilute
It releases, and with being saturated aqueous NaHCO3It washes twice, and is washed with brine primary.By organic layer through Na2SO4It is dried, filtered and concentrated
To provide title compound (1158g, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.84 (d, J=
7.7Hz, 1H), 7.19-7.07 (m, 2H), 7.03-6.98 (m, 1H), 6.31 (d, J=8.6Hz, 1H), 5.66-5.54 (m,
1H), 4.86 (d, J=2.8Hz, 1H), 4.26 (qd, J=7.1,1.2Hz, 2H), 4.07 (s, 1H), 3.66 (dq, J=24.9,
7.5Hz, 2H), 3.02 (t, J=2.5Hz, 1H), 2.11 (tt, J=8.4,5.4Hz, 1H), 1.99-1.58 (m, 4H), 1.30
(dd, J=7.5,6.7Hz, 3H), 1.04 (s, 9H), 0.97 (pt, J=8.8,2.6Hz, 2H), 0.81 (ddd, J=9.4,6.3,
3.4Hz, 1H), 0.67-0.52 (m, 1H)；MS(ESI+)m/z 459(M+H)+。
Example 107B
Ethyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -1- ((S)-tetrahydrofuran -
2- carbonyl) pyrrolidines -2- formic acid esters
Example 107A (1.13g, 2.464mmol) and tetrahydrofuran (25mL) are added in 50mL Stainless Steel pressure bottle
'sIn 2800 aqueous slurry of nickel (5.00g, 38.3mmol), and vibrated 16 hours at 50psi hydrogen and 50 DEG C.It will be anti-
It should filter and be concentrated to provide title compound (1.05g, 99%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm
7.87 (s, 1H), 7.14 (dt, J=7.0,3.9Hz, 2H), 7.04 (dt, J=4.7,3.3Hz, 1H), 5.81 (s, 1H), 4.56
(s, 1H), 4.17 (q, J=7.1Hz, 2H), 4.07 (s, 1H), 3.83 (dd, J=6.9,2.2Hz, 1H), 3.68 (q, J=
7.3Hz, 1H), 3.60 (dddd, J=6.6,4.1,2.7,1.4Hz, 2H), 2.07 (t, J=2.6Hz, 1H), 1.92 (s, 1H),
1.84-1.53 (m, 3H), 1.25 (t, J=7.1Hz, 3H), 1.01 (s, 9H), 0.97-081 (m, 2H), 0.67 (dddd, J=
12.0,10.6,5.8,3.2Hz, 2H)；MS(ESI+)m/z 429(M+H)+。
Example 107C
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- cyclopropyl phenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
By example 107B (210.5mg, 0.491mmol) and 5- cyclobutyl -2- methoxyl group cigarette aldehyde (133.3mg,
It 0.697mmol) is dissolved in dichloroethanes (6mL).It adds sodium triacetoxy borohydride (207.9mg, 0.981mmol), and will
Reaction is stirred 1 hour at ambient temperature.By reaction with methylene chloride (35mL) dilute, and be saturated aqueous sodium bicarbonate
(35mL) quenching, and stir 30 minutes.Organic layer is concentrated and extracts water layer with methylene chloride (2x35mL).By having for merging
Machine layer is through Na2SO4It is dried, filtered and concentrated.Residue is purified by silica gel chromatography (10% in methylene chloride to
25% ethyl acetate), to provide title compound (165.9mg, 56%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C)
δ ppm 7.88 (s, 1H), 7.75 (d, J=2.5Hz, 1H), 7.15 (s, 2H), 7.10 (d, J=2.4Hz, 1H), 708-6.97
(m, 1H), 5.87 (s, 1H), 4.73 (s, 1H), 4.11 (q, J=7.1Hz, 2H), 3.72-3.30 (m, 10H), 3.24 (dd, J=
14.3,7.3Hz, 1H), 2.39 (s, 1H), 2.33-2.18 (m, 2H), 2.11-1.53 (m, 8H), 1.18 (t, J=7.1Hz,
3H), 1.02 (s, 9H), 0.87 (tdd, J=9.4,5.8,4.0Hz, 1H), 0.76 (tt, J=8.6,4.7Hz, 1H), 0.61
(dtd, J=9.5,5.6,4.0Hz, 1H), 0.50-0.40 (m, 1H)；MS(ESI+)m/z 604(M+H)+。
Example 107D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- cyclopropyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 107C (161.9mg, 0.268mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 1.0mL,
1.0mmol) and reaction is heated to 50 DEG C and continues 16 hours.By reaction by the addition aqueous HCl of 1M (1mL) quenching, diformazan is used
Base sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in double trifluoroacetates
Title compound (130.7mg, 61%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.82 (dd, J=
14.5,4.2Hz, 2H), 7.18 (td, J=3.8,2.2Hz, 3H), 7.07 (dt, J=6.2,3.4Hz, 1H), 5.91 (d, J=
6.6Hz, 1H), 4.67 (d, J=1.4Hz, 1H), 4.12 (s, 2H), 3.73-3.54 (m, 7H), 3.46-3.33 (m, 1H), 3.28
(d, J=14.2Hz, 1H), 2.48 (s, 1H), 2.34-2.18 (m, 2H), 2.05-1.41 (m, 8H), 1.03 (s, 9H), 0.95-
0.84 (m, 1H), 0.83-0.73 (m, 1H), 0.62 (dtd, J=9.3,5.5,3.9Hz, 1H), 0.52 (dtd, J=9.5,5.6,
3.9Hz, 1H)；MS(ESI+)m/z 576(M+H)+。
Example 108
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- ring
Propyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
By example 107B (103.2mg, 0.241mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (84.9mg,
It 0.442mmol) is dissolved in methanol (2mL).It adds sodium cyanoborohydride (74.5mg, 1.186mmol), and will react in environment
At a temperature of stir 17 hours.It adds aqueous LiOH (1M, 1.0mL, 1.0mmol) and reaction is heated to 50 DEG C and continue 16 hours.
It by reaction by addition trifluoroacetic acid (0.2mL) quenching, is diluted with dimethyl sulfoxide (1mL), filter and uses trifluoroacetic acid side
Method is purified by reverse phase, to provide the title compound (108.2mg, 56%) for being in trifluoroacetate.1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.79 (s, 1H), 7.22 (dt, J=8.4,3.3Hz, 3H), 7.13-7.07 (m, 1H),
7.02 (d, J=2.6Hz, 1H), 6.77 (d, J=8.6Hz, 1H), 5.94 (s, 1H), 4.67 (d, J=1.3Hz, 1H), 4.15
(s, 1H), 3.85-3.57 (m, 4H), 3.49 (s, 3H), 3.36-3.29 (m, 1H), 2.57 (s, 1H), 1.97 (dt, J=8.5,
5.6Hz, 1H), 1.78 (ddt, J=11.8,8.5,5.0Hz, 2H), 1.67 (s, 2H), 1.21 (d, J=0.8Hz, 9H), 1.04
(s, 9H), 0.89 (dddd, J=12.9,9.2,6.2,3.2Hz, 1H), 0.77 (tdd, J=9.1,5.7,4.0Hz, 1H), 0.61
(dtd, J=9.5,5.6,4.0Hz, 1H), 0.50 (dtd, J=9.5,5.6,4.0Hz, 1H)；MS(ESI+)m/z 577(M+H)+。
Example 109
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
5- (2- aminomethyl phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 109A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -4- nitro -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) -5- is (adjacent
Tolyl) pyrrolidines -2- formic acid esters
(S)-oxinane -2- formic acid (389mg, 2.99mmol) is dissolved in methylene chloride (10mL).Add oxalyl chloride
(1.5mL, 2M, 3.00mmol) then adds n,N-Dimethylformamide (25 μ L).It is small that stirring 3 at ambient temperature will be reacted
When, it is concentrated at this time, is re-dissolved in methylene chloride (2mL) and is concentrated again.Residue is absorbed in methylene chloride
In (3x2mL), and core 10 (1.00g, 2.99mmol) and triethylamine (1.0mL, 7.17mmol) are added in methylene chloride
In solution in (10mL).Reaction is stirred 17 hours at ambient temperature.After this, by mixture CH2Cl2(100mL) is dilute
It releases, and with being saturated aqueous NaHCO3It washes twice, and is washed with brine primary.By organic layer through Na2SO4It is dried, filtered and concentrated
To provide title compound (1.33g, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.90 (d, J=7.6Hz, 1H), 7.19-7.09 (m, 3H), 6.01 (m, 1H),
5.56 (d, J=9.1Hz, 1H), 4.77 (m, 1H), 4.24 (q, J=7.0Hz, 2H), 3.79 (m, 1H), 2.99 (t, J=
3.1Hz, 1H), 2.40 (s, 3H), 1.71-1.62 (m, 1H), 1.51 (m, 1H), 1.45-1.26 (m, 8H), 1.02 (s, 9H),
0.83 (m, 1H)；MS(ESI+)m/z 447(M+H)+。
Example 109B
Ethyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) -5- is (adjacent
Tolyl) pyrrolidines -2- formic acid esters
Replace example 107A with example 109A, title compound is prepared according to program described in example 107B.1H NMR
(400MHz, DMSO-d6) δ ppm 7.87 (m, 1H), 7.15 (m, 3H), 5.46 (m, 1H), 4.47 (m, 1H), 4.16 (m, 2H),
3.80-3.68 (m, 2H), 2.32 (s, 3H), 2.01 (t, J=2.8Hz, 1H), 1.66 (m, 1H), 1.54-1.30 (m, 5H),
1.27-1.19 (m, 3H), 0.99 (s, 9H), 0.80 (m, 2H)；MS(ESI+)m/z 417(M+H)+。
Example 109C
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((2- methoxyl group -5- (1- methyl-cyclobutyl) benzyl) amino) -
1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) -5- (o-tolyl) pyrrolidines -2- formic acid esters
By example 109B (69.1mg, 0.166mmol) and 2- methoxyl group -5- (1- methyl-cyclobutyl) benzaldehyde (intermediate
5,52.6mg, 0.258mmol) it is dissolved in methanol (1mL) and stirs 3 hours at ambient temperature.Add sodium cyanoborohydride
(64.2mg, 1.022mmol), and reaction is stirred for 16 hours at ambient temperature.Reaction is dilute with dimethyl sulfoxide (1mL)
It releases, filter and is purified using ammonium acetate method by reverse phase, to provide title compound (62.9mg, 63%).1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.93 (s, 1H), 7.17 (s, 3H), 6.96 (dd, J=8.4,2.5Hz,
1H), 6.78-6.70 (m, 2H), 5.61 (s, 1H), 469 (s, 1H), 4.13 (qq, J=7.4,3.9Hz, 2H), 3.71 (d, J=
49.1Hz, 1H), 3.55-3.42 (m, 5H), 3.23 (dd, J=13.8,7.1Hz, 1H), 2.35 (s, 1H), 2.22 (t, J=
9.8Hz, 2H), 2.16 (s, 3H), 2.09-1.91 (m, 4H), 1.82-1.72 (m, 2H), 1.72-1.25 (m, 9H), 1.21 (t, J
=7.1Hz, 3H), 1.02 (s, 9H)；MS(ESI+)m/z 605(M+H)+。
Example 109D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -
5- (2- aminomethyl phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 109C (59.9mg, 0.099mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 0.5mL,
0.5mmol) and reaction 50 DEG C are heated to be kept for 16 hours.By reaction by the addition aqueous HCl of 1M (0.5mL) quenching, with two
Methyl sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide in trifluoroacetate
Title compound (58.8mg, 86%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 783 (s, 1H), 7.22
(s, 3H), 7.06 (dd, J=8.5,2.5Hz, 1H), 6.87-6.78 (m, 2H), 5.58 (s, 1H), 4.60 (s, 1H), 3.84-
3.69 (m, 3H), 3.57 (s, 3H), 3.31-3.26 (m, 1H), 2.53 (s, 1H), 2.23 (d, J=10.4Hz, 6H), 2.09-
1.93 (m, 3H), 1.80-1.63 (m, 2H), 1.35 (s, 8H), 1.02 (s, 10H)；MS(ESI+)m/z 577(M+H)+。
Example 110
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Base phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 110A
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -1-
((S)-tetrahydro -2H- pyrans -2- carbonyl) -5- (o-tolyl) pyrrolidines -2- formic acid esters
By example 109B (69.1mg, 0.266mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (46.2mg,
It 0.240mmol) is dissolved in methanol (1mL).It adds sodium cyanoborohydride (49.9mg, 0794mmol), and will react in environment
At a temperature of stir 17 hours.Reaction is diluted with dimethyl sulfoxide (1mL), filter and is carried out using ammonium acetate method by reverse phase
Purifying, to provide title compound (67.1mg, 68%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.94
(s, 1H), 7.17 (s, 3H), 7.14 (dd, J=8.5,2.6Hz, 1H), 6.92 (d, J=2.6Hz, 1H), 6.72 (d, J=
8.5Hz, 1H), 5.61 (s, 1H), 4.70 (s, 1H), 4.14 (qt, J=7.1,3.7Hz, 2H), 3.76 (d, J=11.1Hz,
1H), 3.56-3.43 (m, 5H), 3.38-3.25 (m, 2H), 3.23 (d, J=13.7Hz, 1H), 2.35 (s, 1H), 2.15 (s,
3H), 1.73-1.27 (m, 6H), 1.21 (d, J=4.2Hz, 12H), 1.02 (s, 9H)；MS(ESI+)m/z 593(M+H)+。
Example 110B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- first
Base phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 110A (64.1mg, 0.108mmol) is dissolved in methanol (1mL).Add aqueous LiOH (1M, 1.0mL,
1.0mmol) and reaction is heated to 50 DEG C and continues 16 hours.By reaction by the addition aqueous HCl of 1M (1mL) quenching, diformazan is used
Base sulfoxide (1mL) dilution, is filtered and is purified using trifluoroacetic acid method by reverse phase, to provide the mark for being in trifluoroacetate
It inscribes compound (49.7mg, 68%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.86 (d, J=6.9Hz,
1H), 7.29-7.22 (m, 4H), 7.05 (d, J=2.5Hz, 1H), 6.83 (d, J=8.7Hz, 1H), 5.61 (s, 1H), 4.62
(s, 1H), 3.91-3.74 (m, 4H), 3.60 (s, 3H), 3.52 (s, 1H), 3.33-3.26 (m, 1H), 2.57 (s, 1H), 2.27
(s, 3H), 1.70 (d, J=12.4Hz, 1H), 1.56-1.31 (m, 5H), 1.24 (s, 9H), 1.04 (s, 9H)；MS(ESI+)m/z
565(M+H)+。
Example 111
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- ethylphenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
Example 111A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2- ethylphenyl) -4- nitro -1- ((S)-tetrahydrofuran -2-
Carbonyl) pyrrolidines -2- formic acid esters
At ambient temperature, Xiang Xin 28 (0.5g, 1.435mmol) adds three in the solution in methylene chloride (5.0mL)
(S)-tetrahydrofuran -2- phosgene (0.367g, 2.73mmol) is then added dropwise in 2mL bis- in ethamine (1.100mL, 7.89mmol)
Solution in chloromethanes.Reaction is stirred at room temperature 20 minutes, is then quenched with 10mL saturation aqueous sodium bicarbonate, and will be thick
Residue with the gradient of 0-80% ethyl acetate/heptane carries out chromatography 20 minutes using 24g silicagel column, with provide (2S, 3R, 4S,
5S)-ethyl 3- (tert-butyl) -5- (2- ethylphenyl) -4- nitro -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid
Ester (0.603g, 1.350mmol, 94% yield).1HNMR (500MHz, dimethyl sulfoxide-d6) δ ppm 7.91 (d, J=7.9Hz,
1H), 7.21 (dt, J=13.9,7.4Hz, 2H), 7.12 (t, J=7.5Hz, 1H), 6.02 (s, 1H), 5.58 (d, J=8.2Hz,
1H), 4.83 (s, 1H), 4.32-4.24 (m, 2H), 4.07 (bs, 1H), 3.71 (q, J=7.2Hz, 1H), 3.66 (t, J=
6.9Hz, 1H), 3.06 (t, J=3.0Hz, 1H), 2.84 (q, J=15.4,1H), 2.71 (dq, J=15.4,7.7Hz, 1H),
2.00-1.91 (m, 1H), 1.81 (ddd, J=15.1,7.4,5.6Hz, 1H), 1.68 (s, 1H), 1.32 (t, J=7.1Hz,
3H), 1.28 (t, J=7.5Hz, 3H), 1.05 (s, 9H)；MS(APCI+)m/z 447(M+H)+。
Example 111B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -5- (2- ethylphenyl) -1- ((S)-tetrahydrofuran -2-
Carbonyl) pyrrolidines -2- formic acid esters
Example 111A (602mg, 1.348mmol) and tetrahydrofuran (9.5mL) are added in 50mL pressure bottleIn 2800 aqueous slurry of nickel (1641mg, 12.58mmol), and mixture is vibrated 16 hours under the hydrogen of 50psi.
Reaction is filtered and removes solvent in a vacuum.Rough material is dissolved in 1mL methylene chloride and is loaded on 24g column, 0- is used
The gradient elution of 100% ethyl acetate/heptane 15 minutes, with offer (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -
5- (2- ethylphenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters (481mg, 1.155mmol, 86%
Rate).1HNMR (500MHz, dimethyl sulfoxide-d6) δ ppm 7.92 (d, J=7.4Hz, 1H), 7.27-7.14 (m, 3H), 5.50
(s, 1H), 4.55 (s, 1H), 4.20 (q, J=7.1Hz, 2H), 4.07 (bs, 1H), 3.73 (d, J=6.7Hz, 1H), 3.69 (q,
J=7.3Hz, 1H), 3.62 (d, J=7.6Hz, 1H), 2.74 (dt, J=14.9,7.4Hz, 1H), 266 (dt, J=14.9,
7.6Hz, 1H), 2.08 (s, 1H), 1.95 (s, 1H), 1.79 (tt, J=13.7,6.5Hz, 1H), 1.65 (s, 1H), 1.26 (dt,
J=12.4,7.3Hz, 6H), 1.02 (s, 9H), 0.78 (s, 2H)；MS(APCI+)m/z 417(M+H)+。
Example 111C
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- ethylphenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters
To 5- cyclobutyl -2- methoxyl group cigarette aldehyde (60.6mg, 0.317mmol), example 111B (120mg, 0.288mmol) and
Zinc chloride (II) (39.3mg, 0.288mmol) is the solution in sodium acetate/acetate buffer (pH=4,2mL) in methanol
Middle addition sodium cyanoborohydride (27.2mg, 0.432mmol), and reaction is stirred 2 hours at ambient temperature.Solvent is gone
It removes, and gained residue is subjected to chromatography using 24g silicagel column, with gradient elution 20 minutes of 0-60% ethyl acetate/heptane,
To provide (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- ethylphenyl) -1- ((S)-tetrahydrofuran -2- carbonyl) pyrrolidines -2- formic acid esters (149mg, 0.252mmol,
87% yield).1HNMR (500MHz, dimethyl sulfoxide-d6) δ ppm 7.93 (s, 1H), 7.78 (s, 1H), 7.20 (m, 3H),
7.12 (s, 1H), 5.56 (s, 1H), 4.73 (s, 1H), 4.14 (q, J=7.1Hz, 2H), 3.69 (d, J=7.4Hz, 1H), 3.60
(s, 3H), 3.43 (ddd, J=17.5,14.8,7.6Hz, 3H), 3.24 (dd, J=14.3,6.3Hz, 1H), 2.61 (dt, J=
14.9,7.4Hz, 1H), 2.49-2.43 (m, 1H), 2.40 (s, 1H), 2.28 (ddt, J=8.8,5.9,3.7Hz, 2H), 2.12-
1.92 (m, 4H), 1.90-1.74 (m, 2H), 1.66 (s, 1H), 1.21 (t, J=7.1Hz, 3H), 1.15 (t, J=7.5Hz,
3H), 1.03 (s, 9H)；MS(ESI+)m/z 593(M+H)+。
Example 111D
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5-
(2- ethylphenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
To example 111C (148mg, 0.250mmol) in tetrahydrofuran (0.760mL), methanol (0.760mL) and water
Lithium hydroxide H is added in the solution of (0.760mL)2O (73.5mg, 1.751mmol), and it is small to react the heating 16 at 45 DEG C
When.Solvent is removed under nitrogen flowing.Water (0.5mL) is added in rough material, and by the mixture aqueous HCl of 1M
(1.63mL) is acidified to pH~6, is extracted with dichloromethane, and solvent is evaporated in vacuo.Gained rough material is used into 4g silicon
Rubber column gel column carries out chromatography 10 minutes with the gradient of 0-10% ethanol/methylene, to provide (2S, 3S, 4S, 5S) -3- (tert-butyl) -
4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) amino) -5- (2- ethylphenyl) -1- ((S)-tetrahydrofuran -2-
Carbonyl) pyrrolidines -2- formic acid (57mg, 0.101mmol, 40.4% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm
7.88 (d, J=7.7Hz, 1H), 7.76 (d, J=2.4Hz, 1H), 7.23-7.08 (m, 4H), 5.51 (s, 1H), 4.65-4.57
(m, 1H), 4.10 (s, 1H), 3.68 (t, J=7.0Hz, 1H), 3.59 (s, 3H), 3.48 (d, J=14.5Hz, 1H), 3.44-
3.32 (m, 2H), 3.23 (d, J=14.4Hz, 1H), 2.60 (dq, J=15.0,7.5Hz, 2H), 2.42 (d, J=7.4Hz,
1H), 2.40-2.35 (m, 1H), 2.31-2.19 (m, 2H), 2.02-1.89 (m, 4H), 1.88-1.74 (m, 2H), 1.64 (s,
1H), 1.12 (t, J=7.5Hz, 3H), 0.99 (s, 9H)；MS(APCI+)m/z 565(M+H)+。
Example 112
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (1- methyl ring fourth
Base) phenyl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid
By example 107B (101.2mg, 0.236mmol) and 2- methoxyl group -5- (1- methyl-cyclobutyl) benzaldehyde (intermediate
5,75.2mg, 0.368mmol) it is dissolved in methanol (2mL).It adds sodium cyanoborohydride (47.4mg, 0.754mmol), and will
Reaction is stirred 17 hours at ambient temperature.It adds aqueous LiOH (1M, 1.0mL, 1.0mmol) and reaction is heated to 50 DEG C and hold
It is 16 hours continuous.It by reaction by addition trifluoroacetic acid (0.2mL) quenching, is diluted with dimethyl sulfoxide (1mL), filter and uses three
Fluoroacetic acid method is purified by reverse phase, to provide the title compound (101.9mg, 61%) for being in trifluoroacetate.1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.79 (t, J=4.6Hz, 1H), 7.25-7.17 (m, 2H), 7.13-
7.07 (m, 1H), 7.04 (dd, J=8.4,2.4Hz, 1H), 6.84 (d, J=2.4Hz, 1H), 6.78 (d, J=8.5Hz, 1H),
5.94 (d, J=6.5Hz, 1H), 4.67 (d, J=1.3Hz, 1H), 4.15 (s, 1H), 3.84-3.59 (m, 4H), 3.50 (s,
3H), 3.32 (d, J=13.6Hz, 1H), 2.56 (s, 1H), 2.28-2.16 (m, 2H), 2.10-1.90 (m, 4H), 1.85-1.59
(m, 5H), 1.34 (s, 3H), 1.04 (s, 9H), 0.95-0.83 (m, 1H), 0.83-0.73 (m, 1H), 0.61 (dtd, J=9.3,
5.6,3.9Hz, 1H), 0.51 (dtd, J=9.4,5.6,3.9Hz, 1H)；MS(ESI+)m/z 589(M+H)+。
Example 113
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl]
Amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 113A
Ethyl (2S, 3R, 4S, 5S) -5- (2- bromophenyl) -3- (tert-butyl) -4- nitro -1- ((S)-tetrahydro -2H- pyrans -
2- carbonyl) pyrrolidines -2- formic acid esters
(S)-oxinane -2- formic acid (425mg, 3.27mmol) is dissolved in methylene chloride (10mL).Add oxalyl chloride
(1.7mL, 2M, 3.40mmol) then adds n,N-Dimethylformamide (25 μ L).It is small that stirring 3 at ambient temperature will be reacted
When.Mixture is concentrated, is re-dissolved in methylene chloride (2mL), and be concentrated again.Residue is absorbed in methylene chloride
In (3x2mL), and core 25 (1.30g, 3.26mmol) and triethylamine (1.5mL, 10.76mmol) are added in methylene chloride
In solution in (10mL).Reaction is stirred 17 hours at ambient temperature.After this, by mixture CH2Cl2(100mL) is dilute
It releases, and with being saturated aqueous NaHCO3It washes twice, and is washed with brine primary.By organic layer through Na2SO4It is dried, filtered and concentrated
To provide title compound (1.66g, 100%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.99 (dd, J
=7.8,1.7Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.34 (t, J=7.5Hz, 1H), 7.28-7.19 (m, 1H), 6.14
(s, 1H), 5.51 (dd, J=8.7,2.1Hz, 1H), 4.86 (s, 1H), 4.26 (q, J=7.1Hz, 2H), 3.81 (dtd, J=
11.4,4.2,3.7,1.5Hz, 1H), 3.61-3.26 (m, 2H), 2.99 (t, J=2.6Hz, 1H), 1.75-1.34 (m, 6H),
1.30 (t, J=7.1Hz, 3H), 1.03 (s, 9H)；MS(ESI+)m/z 511&513(M+H)+。
Example 113B
Ethyl (2S, 3S, 4S, 5S) -4- amino -5- (2- bromophenyl) -3- (tert-butyl) -1- ((S)-tetrahydro -2H- pyrans -
2- carbonyl) pyrrolidines -2- formic acid esters
Example 113A (1.66g, 3.25mmol) is dissolved in tetrahydrofuran (15mL), and add zinc (2.122g,
32.5mmol), then acetic acid (1.858mL, 32.5mmol) is added.Reaction is heated to 65 DEG C and continues 2 hours.Reaction is filtered
And be concentrated, it is then purified using the gradient of 50%-100% ethyl acetate in methylene chloride, to provide title compound
Object (901.2mg, 58% yield).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.95 (s, 1H), 7.59 (d, J
=8.0Hz, 1H), 7.35 (t, J=7.3Hz, 1H), 7.18 (t, J=7.7Hz, 1H), 5.58 (s, 1H), 4.53 (s, 1H),
4.18 (qd, J=7.0,2.6Hz, 2H), 3.86-3.72 (m, 2H), 3.44-3.15 (m, 2H), 2.03 (t, J=2.4Hz, 1H),
1.69 (d, J=12.3Hz, 1H), 1.62-1.30 (m, 5H), 1.25 (t, J=7.0Hz, 3H), 1.00 (s, 9H)；MS(ESI+)
m/z 481&483(M+H)+。
Example 113C
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl]
Amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
By example 113B (118.9mg, 0.247mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (70.9mg,
It 0.369mmol) is dissolved in methanol (2mL).It adds sodium cyanoborohydride (37.8mg, 0.602mmol), and will react in environment
At a temperature of stir 17 hours.It adds aqueous LiOH (1M, 1.0mL, 1.0mmol) and reaction is heated to 50 DEG C and continue 16 hours.
It by reaction by addition trifluoroacetic acid (0.2mL) quenching, is diluted with dimethyl sulfoxide (1mL), filter and uses trifluoroacetic acid side
Method is purified by reverse phase, to provide the title compound (110.4mg, 60%) for being in trifluoroacetate.1HNMR (400MHz,
Dimethyl sulfoxide-d6, 120 DEG C) δ ppm 7.94 (d, J=7.7Hz, 1H), 7.63-7.56 (m, 1H), 7.38 (t, J=7.5Hz,
1H), 7.25-7.20 (m, 1H), 7.18 (dd, J=8.6,2.6Hz, 1H), 7.01 (d, J=2.6Hz, 1H), 6.77 (d, J=
8.6Hz, 1H), 5.67 (s, 1H), 4.62 (d, J=1.5Hz, 1H), 3.85-3.63 (m, 4H), 3.57 (s, 3H), 3.53-3.50
(m, 1H), 3.31 (d, J=13.6Hz, 1H), 2.44 (s, 1H), 1.69 (d, J=12.1Hz, 1H), 1.56-1.33 (m, 5H),
1.21 (s, 9H), 1.00 (s, 9H)；MS(ESI+)m/z 629&631(M+H)+。
Example 114
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [2- methoxyl group -5- (trifluoromethyl) pyridine -
3- yl] amino } -5- Phenylpyrrolidine -2- formic acid
Example 114A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -4- nitro -5- Phenylpyrrolidine -2- first
Acid esters
To (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (core 7,
500mg, 1.561mmol) and triethylamine (0.653mL, 4.68mmol) mixing in the methylene chloride (10mL) of cooling in ice bath
It closes in object and cyclohexanecarbonyl chloride (0.251mL, 1.873mmol) is added dropwise.Mixture is stirred 30 minutes in ice bath and makes its temperature
Heat is to room temperature.It adds methylene chloride (10mL).Mixture is washed with brine, through MgSO4It is dried, filtered and concentrated to provide mark
It inscribes compound (490mg, 72.9% yield), it is used in next step without further purification.LC/MS(APCI+)m/z
431(M+H)+。
Example 114B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- first
Acid esters
It will be added in 50mL pressure bottle in the example 114A (300mg, 0.697mmol) in tetrahydrofuran (10mL)In 2800 aqueous slurry of nickel (2.2g, 16.87mmol).Mixture is vibrated 20 under 50psi hydrogen at ambient temperature
Hour, it filters and is concentrated to provide title compound (280mg, 100% yield).LC/MS(APCI+)m/z 400.93(M+H)+。
Example 114C
(2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base) amino) -5- Phenylpyrrolidine -2- formic acid
By (2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2-
Formic acid esters (example 114B, 100mg, 0.250mmol), bromo- 2- methoxyl group -5- (trifluoromethyl) pyridine of 3- (70.3mg,
0.275mmol), 4- (di-t-butyl phosphino-)-n,N-Dimethylaniline (6.63mg, 0.025mmol), cesium carbonate (96mg,
0.499mmol) and the mixture N of Isosorbide-5-Nitrae-dioxanes (2mL) in the vial2Then purging about 30 minutes adds Pd2 (dba) 3
(tris(dibenzylideneacetone) dipalladium (0), 11.43mg, 0.012mmol).Reaction mixture is used into N again2Purging 10 minutes, then
It is heated 16 hours at 40 DEG C.Mixture is filtered, and is washed with ethyl acetate.Combined organic layer is concentrated.By residue
It is purified by chromatography, the ethyl acetate in heptane is eluted with 0-40%, with offer (2S, 3S, 4S, 5S)-ethyl 3- (uncle
Butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) amino) -5- Phenylpyrrolidine -2-
Formic acid esters is dissolved in methanol (4mL) and the aqueous HCl of aqueous 4M (1mL).Mixture is stirred overnight at 40 DEG C.It will be molten
Agent removal, and residue is adjusted to pH~5 with the aqueous HCl of 1N.Gained is mixed with trifluoroacetic acid method using reversed-phase HPLC
The purifying that object carries out provides (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- in trifluoroacetate
((2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl) amino) -5- Phenylpyrrolidine -2- formic acid (46mg, 0.084mmol,
33.6% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.54-7.44 (m, 3H), 7.09 (dd, J=8.1,
6.5Hz, 2H), 7.03 (t, J=7.2Hz, 1H), 6.97 (d, J=2.1Hz, 1H), 5.35 (d, J=7.2Hz, 1H), 4.85 (d,
J=10.5Hz, 1H), 4.54 (s, 1H), 4.45 (d, J=3.7Hz, 1H), 3.74 (s, 3H), 2.26 (t, J=3.7Hz, 1H),
2.17 (s, 1H), 1.64 (s, 2H), 1.45 (s, 2H), 1.29-1.07 (m, 4H), 1.04 (s, 9H), 1.02 (s, 2H)；MS(ESI
+)m/z 548.2(M+H)+。
Example 115
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 115A
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclopropyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- isopropyl phenyl) pyrrolidines -2- formic acid esters
By example 61B (0.300g, 0.693mmol), 5- cyclopropyl -2- methoxyl group cigarette aldehyde (0.123g, 0.693mmol) and
Sodium triacetoxyborohydride (0.220g, 1.040mmol) is stirred at room temperature overnight in 1,2- dichloroethanes (3.5mL).So
Mixture and 3.5mL saturated sodium bicarbonate solution are vigorously stirred 30 minutes afterwards.Mixture is extracted with dichloromethane three times.It will
Combined organic extract is through Na2SO4It dries, filters and is concentrated in a vacuum, to provide crude intermediate (2S, 3S, 4S, 5S) -1-
Tert-butyl 2- ethyl 3- (tert-butyl) -4- (((5- cyclopropyl -2- methoxypyridine -3- base) methyl) amino) -5- (2- isopropyl
Phenyl) pyrrolidines -1,2- dicarboxylic acid esters.MS(APCI+)m/z 594.7(M+H).Rough material is dissolved in methylene chloride (2.7mL)
In, and be stirred at room temperature together 4 hours with trifluoroacetic acid (1.3mL, 17.3mmol).Mixture is concentrated in a vacuum, and
Residue is absorbed in methylene chloride, and is washed twice and is washed with brine primary with 1N LiOH aqueous solution.Organic layer is passed through
Na2SO4It dries, filters and is concentrated in a vacuum to provide title compound.1H NMR (400MHz, DMSO-d6)δppm 7.70
(m, 1H), 7.62 (m, 1H), 7.31-7.15 (m, 2H), 7.12 (m, 1H), 6.88 (d, J=2.5Hz, 1H), 4.41 (d, J=
4.9Hz, 1H), 4.14 (q, J=7.0Hz, 2H), 3.64 (s, 3H), 3.62 (m, 1H), 3.25 (d, J=14.3Hz, 1H), 3.14
(m, 1H), 3.06 (dd, J=5.0,1.7Hz, 1H), 2.98 (d, J=14.3Hz, 1H), 2.17 (dd, J=5.8,1.6Hz,
1H), 1.74 (m, 1H), 1.27-1.11 (m, 9H), 0.97 (s, 9H), 0.82 (m, 2H), 0.46 (m, 2H)；MS(ESI+)m/z
494.2(M+H)+。
Example 115B
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclopropyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -5- (2- isopropyl phenyl) -1- ((S)-tetrahydro -2H- pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
By tetrahydro -2H- pyrans -2- formic acid (0.149g, 1.146mmol) at thionyl chloride (1.088mL, 14.90mmol)
Middle reflux 1 hour.Mixture is cooled to room temperature and is concentrated in a vacuum.Excessive thionyl chloride three is expelled with methylene chloride
It is secondary, and by residue with example 115A (0.283g, 0.573mmol) 3mL methylene chloride and pyridine (0.556mL,
Solution processing in 6.88mmol).Reaction is stirred at room temperature overnight.Mixture is diluted with ethyl acetate, and is washed with water
It washs three times and is washed with brine primary.Organic layer is concentrated in a vacuum, and residue is purified by silica gel chromatography, with 0
It is eluted to 20% ethyl acetate-dichloromethane, to provide title compound.1H NMR (400MHz, DMSO-d6)δppm 7.90
(d, J=7.7Hz, 1H), 7.72 (d, J=2.6Hz, 1H), 7.26 (m, 2H), 7.11 (m, 1H), 6.85 (d, J=2.5Hz,
1H), 5.61 (m, 1H), 4.69 (d, J=1.4Hz, 1H), 4.10 (q, J=7.1Hz, 2H), 3.73 (m, 1H), 3.57 (s, 3H),
3.40 (m, 3H), 3.12 (m, 2H), 2.32 (m, 1H), 1.77-1.31 (m, 4H), 1.26 (d, J=6.7Hz, 3H), 1.22-
1.15 (m, 6H), 1.05 (m, 2H), 1.02 (s, 9H), 0.94 (m, 2H), 0.84 (m, 2H), 0.46 (m, 2H)；MS(ESI+)m/z
606.4(M+H)。
Example 115C
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- [2- (third
Alkane -2- base) phenyl] pyrrolidines -2- formic acid
By example 115B (0.054g, 0.089mmol) and lithium hydroxide (1M is aqueous) (1mL, 1mmol) in tetrahydrofuran
It is stirred overnight at 45 DEG C in (1mL) and methanol (1mL).Reaction mixture is diluted with water and is adjusted to pH with the aqueous hydrochloric acid of 1N
2.Mixture is extracted with dichloromethane three times.By combined extract through Na2SO4It dries, filters and is being concentrated in vacuo, and will
Residue is purified by silica gel chromatography, 0 to 5% methanol-ethyl acetate of use elution, to provide title compound.1H NMR
(400MHz, DMSO-d6) δ ppm 7.84 (d, J=7.9Hz, 1H), 7.77-7.70 (m, 1H), 7.27 (m, 2H), 7.11 (t, J
=7.5Hz, 1H), 6.89 (m, 1H), 5.59 (m, 1H), 4.62 (d, J=1.4Hz, 1H), 3.73 (m, 1H), 3.56 (s, 3H),
3.53-3.43 (m, 2H), 3.39 (d, J=6.5Hz, 1H), 3.23-3.01 (m, 4H), 2.36 (m, 1H), 1.81-1.31 (m,
6H), 1.26 (d, J=6.8Hz, 3H), 1.04 (d, J=6.9Hz, 3H), 1.01 (s, 9H), 0.89-0.79 (m, 2H), 0.51-
0.43 (m, 2H)；MS(ESI+)m/z 578.3(M+H)+。
Example 116
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
Example 116A
Ethyl (2S, 3R, 4S, 5S) -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -4- nitro -1- ((S)-tetrahydro -2H-
Pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
(S)-oxinane -2- formic acid (161.3mg, 1.24mmol) is dissolved in methylene chloride (5mL).Add oxalyl chloride
(2M, 0.63mL, 1.26mmol) then adds n,N-Dimethylformamide (25 μ L).It is small that stirring 1 at ambient temperature will be reacted
When, it is concentrated at this time, is re-dissolved in methylene chloride (1mL) and is concentrated again.Residue is absorbed in methylene chloride
In (3x1mL), and core 14 (374.7mg, 1.04mmol) and triethylamine (500 μ L, 3.59mmol) are added in methylene chloride
In solution in (10mL).Reaction is stirred 2 hours at ambient temperature.By mixture CH2Cl2(50mL) dilution, and with satisfy
With aqueous NaHCO3It washes twice, and is washed with brine primary.By organic layer through Na2SO4It is dried, filtered and concentrated to provide mark
Inscribe compound.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.87 (dd, J=7.8,1.4Hz, 1H), 7.21-
7.13 (m, 1H), 7.13-7.06 (m, 1H), 6.99 (dd, J=7.7,1.4Hz, 1H), 6.29 (d, J=8.6Hz, 1H), 5.56
(dd, J=8.6,2.1Hz, 1H), 4.85 (s, 1H), 4.32-4.18 (m, 2H), 3.81-3.70 (m, 1H), 3.66-3.44 (m,
1H), 3.13-3.01 (m, 1H), 2.98 (t, J=2.5Hz, 1H), 2.09 (tt, J=8.3,5.3Hz, 1H), 1.71-1.33 (m,
6H), 1.29 (t, J=7.1Hz, 3H), 1.08-0.96 (m, 11H), 0.78 (ddt, J=10.0,4.9,2.1Hz, 1H), 0.73-
0.63 (m, 1H)；MS(ESI+)m/z 473(M+H)+。
Example 116B
Ethyl (2S, 3S, 4S, 5S) -4- amino -3- (tert-butyl) -5- (2- cyclopropyl phenyl) -1- ((S)-tetrahydro -2H-
Pyrans -2- carbonyl) pyrrolidines -2- formic acid esters
Example 116A (394.8mg, 1.162mmol) and tetrahydrofuran (7.5mL) are added in 50mL Stainless Steel pressure resistance
In bottleIn 2800 aqueous slurry of nickel (719.3mg, 5.52mmol), and mixture is shaken at 50psi hydrogen and 50 DEG C
It swings 26 hours.Reaction is filtered and is concentrated to provide title compound.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ
Ppm 7.85 (s, 1H), 7.15 (t, J=4.6Hz, 2H), 7.06-7.00 (m, 1H), 5.78 (s, 1H), 4.52 (d, J=
2.7Hz, 1H), 4.17 (qd, J=7.0,2.1Hz, 2H), 3.86-3.67 (m, 2H), 3.65-3.36 (m, 2H), 3.19 (d, J=
2.7Hz, 1H), 2.02 (t, J=2.4Hz, 1H), 1.71-1.29 (m, 6H), 1.24 (t, J=7.1Hz, 3H), 1.00 (s, 9H),
0.96-0.85 (m, 2H), 0.76-0.57 (m, 2H)；MS(ESI+)m/z 443(M+H)+。
Example 116C
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid
By example 116B (72.2mg, 0.163mmol) and 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde (51.3mg,
It 0.250mmol) is dissolved in methanol (1mL).It adds sodium cyanoborohydride (24.9mg, 0.396mmol), and will react in environment
At a temperature of stir 3 hours.Aqueous LiOH (1M, 0.5mL, 0.5mmol) is added in reaction.Then reaction is heated to 50 DEG C
Continue 16 hours.The reaction aqueous HCl of 1M (0.5mL) is quenched, is diluted with dimethyl sulfoxide (1mL), and filter.Gained is residual
Excess is purified using trifluoroacetic acid method by reversed-phase HPLC, to provide the title compound for being in trifluoroacetate.1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 8.31 (d, J=2.0Hz, 1H), 7.92-7.81 (m, 1H), 7.54 (d, J
=2.5Hz, 1H), 7.16 (qt, J=7.3,4.0Hz, 2H), 7.03 (dd, J=7.0,2.1Hz, 1H), 5.88 (d, J=
6.4Hz, 1H), 4.61 (d, J=1.5Hz, 1H), 3.75 (s, 4H), 3.64-3.51 (m, 4H), 3.27 (d, J=14.9Hz,
1H), 2.38 (s, 1H), 1.85 (tt, J=8.6,5.5Hz, 1H), 1.71-1.62 (m, 1H), 1.59-1.06 (m, 5H), 1.00
(s, 9H), 0.95-0.86 (m, 1H), 0.86-0.74 (m, 1H), 0.68 (dtd, J=9.5,5.6,4.0Hz, 1H), 0.49 (dt,
J=10.2,5.1Hz, 1H)；MS(ESI+)m/z 604(M+H)+。
Example 117
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
Example 117A
Ethyl (2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) ammonia
Base) -1- (cyclohexane carbo) -5- (2- isopropyl phenyl) pyrrolidines -2- formic acid esters
Example 68B (101.2mg, 0.199mmol) is dissolved in methylene chloride (2mL).Addition triethylamine (0.1mL,
0.717mmol), then cyclohexanecarbonyl chloride (67.5mg, 0.460mmol) is added.Reaction is concentrated and uses ammonium acetate method
It is purified by reverse phase, to provide title compound.1H NMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.89
(s, 1H), 7.73 (d, J=2.4Hz, 1H), 7.26 (dd, J=18.5,7.4Hz, 2H), 7.15-7.07 (m, 2H), 5.40 (d, J
=6.4Hz, 1H), 4.63 (s, 1H), 4.11 (qd, J=7.0,1.1Hz, 2H), 3.56 (s, 3H), 3.48-3.31 (m, 3H),
3.20 (dd, J=14.2,6.2Hz, 1H), 3.09 (hept, J=6.7Hz, 1H), 2.39 (s, 1H), 2.30-2.18 (m, 2H),
2.02-1.77 (m, 4H), 1.66-1.40 (m, 4H), 1.23 (d, J=6.8Hz, 6H), 1.18 (t, J=7.1Hz, 3H), 1.07
(d, J=6.8Hz, 3H), 1.02 (s, 9H)；MS(ESI+)m/z 618(M+H)+。
Example 117B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
(cyclohexane carbo) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
It will be in the example 117A (92.9mg, 0.150mmol) and lithium hydroxide in tetrahydrofuran (1mL) and methanol (1mL)
(1M is aqueous) (1.0mL, 1.0mmol) is stirred 16 hours at 50 DEG C.The reaction mixture aqueous HCl of 1.2mL 1N is acidified,
And it is concentrated in a vacuum.Residue is purified using trifluoroacetic acid method by RP chromatography, to provide in double trifluoros
The title compound of acetate.1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.81-7.72 (m, 2H), 7.30 (dd, J=
7.9,1.5Hz, 1H), 7.24 (td, J=7.5,1.4Hz, 1H), 7.16 (d, J=2.4Hz, 1H), 7.15-7.08 (m, 1H),
5.41 (d, J=6.5Hz, 1H), 4.78-4.42 (m, 1H), 3.56 (s, 5H), 3.46 (d, J=6.5Hz, 1H), 3.43-3.32
(m, 1H), 3.25 (d, J=14.2Hz, 1H), 3.08 (p, J=6.8Hz, 1H), 2.43 (s, 1H), 2.25 (dddd, J=10.6,
8.6,4.5,2.1Hz, 2H), 2.04-1.89 (m, 3H), 1.89-1.76 (m, 1H), 1.71-1.42 (m, 4H), 1.23 (d, J=
6.7Hz, 9H), 1.07 (d, J=6.8Hz, 3H), 1.02 (s, 9H)；MS(ESI+)m/z 590(M+H)+。
Example 118
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2,2- dimethyl -2,3- dihydro -1- benzo furans
Mutter -7- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid
Example 118A
(2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (2,2- dimethyl -2,3- dihydrobenzenes
And furans -7- base) -4- nitro-pyrrole alkane -2- formic acid esters
To (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -5- (2,2- dimethyl -2,3- Dihydrobenzofuranes -7- base) -
4- nitro-pyrrole alkane -2- formic acid esters (core 57,2.0g, 5.12mmol) and triethylamine (2.142mL, 15.37mmol) are in dichloromethane
Cyclohexanecarbonyl chloride (0.754mL, 5.63mmol) of the addition in ice bath in solution in alkane (10mL).By the mixture 0
DEG C stirring 30 minutes.Add methylene chloride (50mL) and the aqueous NH of saturation4Cl (20mL), and organic layer is separated and is washed with salt
It washs.Organic layer is concentrated and purifies residue via chromatography on 40g silicagel column, with ethyl acetate in hexane with 0-
60% gradient elution, to provide title compound.MS(APCI+)m/z 501.5(M+H)+。
Example 118B
(2S, 3S, 4S, 5S)-ethyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (2,2- dimethyl -2,3-
Dihydrobenzofuranes -7- base) pyrrolidines -2- formic acid esters
To in 50mL pressure bottleExample 118A is added in 2800 aqueous slurry of nickel (1.5g, 11.50mmol)
(500mg, 0.999mmol) and tetrahydrofuran (10mL).Mixture is vibrated 16 hours in 60psi hydrogen and at room temperature.It will mix
Close object filtering.Filter cake is washed with methanol.Filtrate is concentrated under stress to provide title compound.MS(APCI+)m/z 471
(M+H)+。
Example 118C
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2,2- dimethyl -2,3- dihydro -1- benzo furans
Mutter -7- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid
By 2- methoxyl group -5- (trifluoromethyl) cigarette aldehyde [CAS#58002-88-9] (28.8mg, 0.140mmol), example
The mixture of 118B (60mg, 0.127mmol) and zinc chloride (II) (17.37mg, 0.127mmol) merges in 4M acetic acid/acetic acid
Sodium is in the buffer soln in methanol (2mL).Mixture is stirred at room temperature 10 minutes.Add pure sodium cyanoborohydride
(13.13mg, 0.209mmol), and mixture is stirred at room temperature 1 hour.Solvent is removed under stress, and by residue
Purified via chromatography, the ethyl acetate/methanol (10: 1) in heptane with the gradient elution of 0-40%, with obtain (2S,
3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) amino) -1- (hexamethylene
Carbonyl) -5- (2,2- dimethyl -2,3- Dihydrobenzofuranes -7- base) pyrrolidines -2- formic acid esters, it is concentrated.Gained ester is molten
It is stirred 4 hours in the methanol (2mL) with the aqueous LiOH solution (0.5mL) of 6M, and at 45 DEG C.Solvent is removed, and is added
Add water (0.5mL).PH is adjusted to about 4-5 with 1M aqueous HCl.The purifying carried out using trifluoroacetic acid method via reversed-phase HPLC
Provide the title compound in trifluoroacetate.1H NMR (400MHz, DMSO-d6) δ ppm 8.30 (d, J=2.4Hz, 1H),
7.58 (s, 1H), 7.55 (s, 1H), 7.07 (d, J=7.2Hz, 1H), 6.77 (t, J=7.5Hz, 1H), 5.29 (d, J=
7.2Hz, 1H), 4.42 (d, J=3.2Hz, 1H), 3.80 (s, 3H), 3.56 (s, 1H), 3.46 (dd, J=7.2,3.2Hz, 2H),
3.35 (s, 1H), 2.35 (t, J=3.2Hz, 1H), 2.20 (s, 1H), 1.65 (d, J=9.4Hz, 2H), 1.59 (s, 1H), 1.49
(d, J=9.8Hz, 2H), 1.41 (s, 3H), 1.36 (s, 3H), 1.27-1.04 (m, 7H), 0.96 (s, 9H)；MS(ESI+)m/z
632(M+H)+。
Example 119
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] (methyl) ammonia
Base } -1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid
By example 73 (50mg, 84 μm of ol), 37% aqueous formaldehyde (40 μ L, 0.54mmol [containing about 10% methanol]), three
Ethamine (60 μ L, 0.43mmol) and sodium triacetoxy borohydride (54mg, 0.25mmol) are placed in n,N-Dimethylformamide
In (300 μ L).More than six hours are stirred at room temperature in mixture.Add again sodium triacetoxy borohydride (18mg,
0.08mmol) and n,N-Dimethylformamide (100 μ L), and the mixture was stirred overnight.Mixture will be used into methanol dilution, and
[Waters XBridge is purified by reversed-phase HPLCTM5 μm of OBD columns of C18,30 × 100mm, flow velocity 40mL/ minutes,
The acetonitrile of 20% to 80% gradient in 0.1% aqueous trifluoroacetic acid] to provide title compound.1H NMR (400MHz,
DMSO-d6, 120 DEG C) δ ppm 7.94 (d, J=7.8Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 7.36 (d, J=7.8Hz,
1H), 7.17 (dd, J=7.8,7.3Hz, 1H), 6.94 (dd, J=7.8,7.3Hz, 1H), 6.17-6.14 (m, 1H), 5.68 (d,
J=9.7Hz, 1H), 4.72 (d, J=2.4Hz, 1H), 3.94-3.90 (m, 1H), 3.77 (s, 3H), 3.76-3.71 (m, 1H),
3.68-3.58 (m, 1H), 3.35-3.13 (m, 6H), 2.54-2.51 (m, 1H), 2.24-2.14 (m, 2H), 2.00-1.79 (m,
7H), 1.73-1.55 (m, 2H), 1.45-1.25 (m, 9H), 1.04 (s, 9H)；MS(ESI+)m/z 606(M+H)+。
Example I-121
(2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -5- (pyrrolidin-1-yl)
Benzyl) amino) -5- Phenylpyrrolidine -2- formic acid
Example I-121-A
(2S, 3S, 4S, 5S) -4- ((the bromo- 2- methoxy-benzyl of 5-) amino) -3- (tert-butyl) -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid
Replace 5- (tert-butyl)-Benzaldehyde,2-methoxy with the bromo- Benzaldehyde,2-methoxy of 5-, according to described in example 7C
Program prepares title compound.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.62-7.53 (m, 2H), 7.32
(t, J=7.4Hz, 2H), 7.28-7.20 (m, 2H), 7.00 (d, J=2.6Hz, 1H), 6.77 (d, J=8.7Hz, 1H), 5.18
(d, J=6.9Hz, 1H), 4.50 (d, J=2.8Hz, 1H), 4.12 (q, J=7.1Hz, 2H), 3.56 (s, 3H), 3.46-3.41
(m, 1H), 3.38 (d, J=14.3Hz, 1H), 3.29 (d, J=14.3Hz, 1H), 2.33-2.11 (m, 2H), 1.63 (d, J=
9.6Hz, 2H), 1.47 (s, 2H), 1.20 (t, J=7.1Hz, 9H), 0.97 (s, 9H)；MS (ESI+) m/z 599.2 and 601.2
(M+H)+。
Example I-121-B
(2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -5- (pyrrolidin-1-yl)
Benzyl) amino) -5- Phenylpyrrolidine -2- formic acid
Into 4mL bottle be packed into potassium tert-butoxide (9.36mg, 2.5 equivalents, 0.08mmol), [4,5- bis- chloro- 1,3- are bis- for dichloro
(2,6- bis- -3- amyl phenyl) imidazoles -2- subunit] (3- chloropyridine base) palladium (II) (PEPPSI-IPentCl, 2.87mg,
10mol%, 0.003mmol) and stirring rod.Bottle is covered into dottle pin lid and in N2Flow down flushing.Via syringe, 170 μ are added
The pre-weighed bottle of the 0.6mmol of L, the bottle contain in 1mL dimethoxyethane solution pyrrolidines (71.1mg, 1.5
Equivalent, 0.05mmol).By (2S, 3S, 4S, 5S)-ethyl 4- ((the bromo- 2- methoxy-benzyl of 5-) amino) -3- (tertiary fourth of 500 μ L
Base) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters (example I-121-A, 20mg, 0.03mmol) solution addition
To in the bottle containing Pd complex compound.Bottle is placed in 90 DEG C of heated/stirreds to stay overnight.After the completion, rough material is concentrated to dryness.To
In dry rough material, the 1M aqueous solution of the 1500 μ L of 250 μ L tetrahydrofurans and LiOH in 75% methanol is added.By bottle
It covers to be placed in again and be stirred 1 hour under heating (60 DEG C).After complete hydrolysis, by rough material by being filled with 300mg diatom
The filter cylinder of soil.Cylinder is washed twice with 500 μ L methanol.Then by material again in N2Lower drying.Dry rough material is molten again
Solution is in dimethyl sulfoxide/CH of 1400 μ L3In CN solution (1: 1v/v), and purified using reversed-phase HPLC, with acquisition (2S,
3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- ((2- methoxyl group -5- (pyrrolidin-1-yl) benzyl) amino) -5-
Phenylpyrrolidine -2- formic acid.(3.8mg, 16.1% isolated yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm
7.58-7.52 (m, 2H), 7.44-7.37 (m, 2H), 7.36-7.32 (m, 1H), 6.78-6.75 (m, 1H), 6.49-6.45 (m,
1H), 6.32-6.30 (m, 1H), 5.37-5.34 (m, 1H), 4.54 (d, J=1.8Hz, 1H), 3.89-3.86 (m, 1H), 3.76
(d, J=13.2Hz, 1H), 3.49 (s, 3H), 3.13-3.10 (m, 5H) 1.94-1.90 (m, 3H), 1.66-1.59 (m, 2H),
1.55-1.47 (m, 2H), 1.27-1.18 (m, 2H), 1.18-1.15 (m, 1H), 1.12-1.04 (m, 1H), 1.02 (s, 1H),
1.01 (s, 9H), 0.99-0.97 (m, 3H)；MS(APCI+)m/z 590.6(M+H)+。
Example I-244
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(oxygen
Azetidine -3- base) oxygroup] carbonyl } -5- Phenylpyrrolidine -2- formic acid
Example I-244-A
(2S, 3S, 4S, 5S) -2- ethyl 1- oxetanes -3- base 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy
Base benzyl) amino) -5- Phenylpyrrolidine -1,2- dicarboxylic acid esters
Phosgene (15wt.% is in toluene) (677mg, 1.026mmol) is cooled to 0 DEG C, with oxetanes -3- alcohol
(38mg, 0.513mmol) is in CH2Cl2Solution processing in (about 0.5mL), is handled with triethylamine (71.5 μ l, 0.513mmol),
It is stirred at room temperature 30 minutes, is diluted with methyl tertiary butyl ether(MTBE), stirred 5 minutes and filter to remove solid.Filtrate is concentrated.It will
Residue CH2Cl2(1mL) dilution, to obtain 0.5M oxetanes -3- base chloro-formate in CH2Cl2In theory it is molten
Liquid.A part (0.1mL, 0.05mmol) of the 0.5M solution is added to (2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4-
((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- Phenylpyrrolidine -2- formic acid esters (example 34D, 31mg, 0.066mmol)
In CH2Cl2In solution in (0.2mL).Mixture is stirred at room temperature 30 minutes, then is used in CH2Cl2(0.1mL,
0.5M oxetanes -3- base chloro-formate processing in 0.05mmol), is stirred 30 minutes, and in ethyl acetate (30mL) and
It is saturated NaHCO3It is distributed between aqueous solution (5mL).Ethyl acetate layer is washed with brine, dry (MgSO4), it filters, concentration, and
And chromatography is carried out on silica gel, 50% to 100% [9: 1CH in heptane2Cl2: ethyl acetate] gradient elution, to mention
For title compound (29mg, 0.051mmol, 77% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.55 (d, J
=7.2Hz, 2H), 7.32 (t, J=7.4Hz, 2H), 7.24 (t, J=7.2Hz, 1H), 7.14 (dd, J=8.5,2.5Hz, 1H),
6.93 (d, J=2.5Hz, 1H), 6.74 (d, J=8.5Hz, 1H), 5.23 (p, J=6.2,5.8Hz, 1H), 5.09 (d, J=
6.8Hz, 1H), 4.65 (t, J=6.8Hz, 1H), 4.61 (t, J=6.6Hz, 1H), 4.41 (d, J=2.7Hz, 1H), 4.25-
4.22 (m, 1H), 4.19-4.11 (m, 3H), 3.54 (s, 3H), 3.52-3.44 (m, 2H), 3.35-3.29 (m, 1H), 2.40 (t,
J=2.6Hz, 1H), 1.24-1.19 (m, 12H), 1.03 (s, 9H)；LC/MS(ESI+)m/z 568(M+H)+。
Example I-244-B
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(oxygen
Azetidine -3- base) oxygroup] carbonyl } -5- Phenylpyrrolidine -2- formic acid
Solution of the example I-244-A (28mg, 0.049mmol) in tetrahydrofuran (about 1mL) is dilute with methanol (about 1mL)
It releases, is handled with the aqueous NaOH of 1M (about 20 drop) and be heated to 55 DEG C and continue 3 hours.Mixture is cooling, with the aqueous HCl of 1M
(2mL) processing, and extracted with ethyl acetate (30mL).Ethyl acetate layer is washed with brine, dry (MgSO4), it filters, concentration
And chromatography is carried out on silica gel, is used in (10: 1: 1 ethyl acetate: HCOOH: H2O 0% to 100% gradient (200: 1 in)
: 1 ethyl acetate: HCOOH: H2O it) elutes, to provide title compound (19mg, 0.035mmol, 71.4% yield).1HNMR
(400MHz, dimethyl sulfoxide-d6) δ ppm 7.54 (d, J=7.4Hz, 2H), 7.35 (t, J=7.5Hz, 2H), 7.28 (t, J=
7.3Hz, 1H), 7.19 (dd, J=8.5,2.5Hz, 1H), 7.00 (d, J=2.4Hz, 1H), 6.78 (d, J=8.6Hz, 1H),
5.26-5.20 (m, 1H), 5.14 (d, J=6.7Hz, 1H), 4.65 (t, J=6.8Hz, 1H), 4.60 (t, J=6.8Hz, 1H),
4.40 (d, J=2.3Hz, 1H), 4.26-4.22 (m, 1H), 4.17-4.13 (m, 1H), 3.63 (d, J=13.6Hz, 1H),
3.60-3.57 (m, 1H), 3.55 (s, 3H), 3.39 (d, J=13.7Hz, 1H), 2.46 (bs, 1H), 1.24 (s, 9H), 1.03
(s, 9H)；LC/MS(ESI+)m/z 539.4(M+H)+。
Example I-246
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(3R) -1- { [(propane -2- base) oxygroup] carbonyl } piperidines -3- carbonyl] pyrrolidines -2- formic acid
Example I-246-A
(R)-tert-butyl 3- ((2S, 3R, 4S, 5S) -3- (tert-butyl) -2- (ethoxy carbonyl) -4- nitro -5- phenyl pyrazoline
Cough up alkane -1- carbonyl) piperidines -1- formic acid esters
By (R)-N-boc- piperidines -3- formic acid (CAS#163438-09-3,0.859g, 3.75mmol) in CH2Cl2(15mL)
In the solution chloro- N of 1-, N, 2- trimethacrylate amine (CAS#26189-59-3,0.826mL, 6.24mmol) processing, in room temperature
It is lower stirring 10 minutes, with (2S, 3R, 4S, 5S)-ethyl 3- (tert-butyl) -4- nitro -5- Phenylpyrrolidine -2- formic acid esters (core 7,
1g, 3.12mmol) in 1: 1 pyridine/tetrahydrofuran (2mL) solution processing.It stirs the mixture for 2 hours.Mixture is dense
Contracting is to remove CH2Cl2.Residue is distributed between ethyl acetate (about 100mL) and 10% citric acid solution (about 25mL).It will
The separation of these layers, and ethyl acetate layer is washed with 10% citric acid solution (about 10mL), with saturation NaHCO3Solution washing, is used
Salt water washing, dry (MgSO4), it filters, concentration, and carry out chromatography on silica gel, 10% to 50% acetic acid in heptane
The gradient elution of ethyl ester, to provide title compound (1.76g, 3.31mmol, 106% yield).1HNMR (400MHz, dimethyl
Sulfoxide-d6) δ ppm 7.63-7.55 (m, 2H), 7.29 (d, J=5.8Hz, 3H), 5.78-5.72 (m, 1H), 5.67 (d, J=
8.7Hz, 1H), 4.73 (d, J=3.2Hz, 1H), 4.28 (q, J=7.0Hz, 2H), 4.01-3.89 (m, 1H), 3.82-3.71
(m, 1H), 3.06 (t, J=3.4Hz, 1H), 2.75-2.60 (m, 2H), 1.49-1.38 (m, 13H), 1.32 (t, J=7.1Hz,
3H), 1.05 (s, 9H)；MS(ESI-)m/z 530(M-H)-。
Example I-246-B
(R)-tert-butyl 3- ((2S, 3S, 4S, 5S) -3- amino -4- (tert-butyl) -5- (ethoxy carbonyl) -2- phenyl pyrazoline
Cough up alkane -1- carbonyl) piperidines -1- formic acid esters
By example I-246-A (1.648g, 3.1mmol) acetic acid (15.97mL, 279mmol) and ethyl acetate (91mL,
Solution in 930mmol) is handled with zinc (3.04g, 46.5mmol), is stirred 1 hour at 55 DEG C, is heated 2 hours at 55 DEG C
And it is stirred at room temperature overnight.Mixture ethyl acetate is diluted and is filtered to remove solid.It concentrates the filtrate to dry.It will be residual
Excess is in ethyl acetate and saturation NaHCO3It is distributed between aqueous solution.Ethyl acetate layer is washed with brine, dry (MgSO4), mistake
Filter, concentration, and chromatography is carried out on silica gel, the gradient elution of 25% to 100% ethyl acetate in heptane, to provide
Title compound (1.59g, 3.17mmol, 102% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm 7.64-7.56
(m, 2H), 7.36 (t, J=7.4Hz, 2H), 7.28 (t, J=7.2Hz, 1H), 5.09 (d, J=7.1Hz, 1H), 4.44 (d, J=
4.1Hz, 1H), 4.20 (q, J=7.0Hz, 2H), 3.89 (d, J=11.4Hz, 1H), 3.79-3.71 (m, 2H), 2.72-2.56
(m, 2H), 2.27 (bs, 1H), 2.08 (bs, 1H), 1.50-1.35 (m, 13H), 1.27 (t, J=7.1Hz, 3H), 1.04 (s,
9H)；LC/MS(ESI+)m/z 502.4(M+H)+。
Example I-246-C
(R)-tert-butyl 3- ((2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) ammonia
Base) -2- (ethoxy carbonyl) -5- Phenylpyrrolidine -1- carbonyl) piperidines -1- formic acid esters
The 100mL scale amount of sodium acetate trihydrate (3.6g, 26.5mmol) and acetic acid (4.58mL, 80mmol) will be contained
Cylinder is dissolved in methanol (50mL), then further uses methanol dilution, total volume is made to reach 100mL.Add into the solution of 10mL
Add example I-246-B (0.522g, 1.040mmol) and 5- (tert-butyl)-Benzaldehyde,2-methoxy (CAS#85943-26-6,
0.26g, 1.352mmol).Acquired solution is handled with zinc chloride (0.142g, 1.040mmol), uses sodium cyanoborohydride
(0.098g, 1.560mmol) processing, and be stirred at room temperature 2 hours.Mixture is diluted with ethyl acetate (100mL), is used in combination
It is saturated NaHCO3Aqueous solution (30mL) washing.These layers are separated and extract aqueous layer with ethyl acetate (25mL).It will merge
Ethyl acetate layer be washed with brine, dry (MgSO4), it filters, concentration, and carry out chromatography on silica gel, is used in heptane
15% to 50% ethyl acetate gradient elution, to provide the pure title compound of 330mg.1HNMR (400MHz, diformazan
Base sulfoxide-d6) δ ppm 7.65-7.54 (m, 2H), 7.34 (s, 3H), 7.14 (dd, J=8.6,2.5Hz, 1H), 6.94 (d, J=
2.3Hz, 1H), 6.75 (d, J=8.6Hz, 1H), 5.22 (d, J=6.5Hz, 1H), 4.56 (d, J=2.7Hz, 1H), 4.14 (q,
J=7.0Hz, 2H), 3.96-3.70 (m, 1H), 3.55 (s, 3H), 3.49 (d, J=13.6Hz, 1H), 3.34 (d, J=
13.6Hz, 1H), 2.71-2.56 (m, 2H), 2.44-2.28 (m, 1H), 1.43 (s, 9H), 1.32-1.18 (m, 16H), 1.02
(s, 9H)；LC/MS(ESI+)m/z 678.4(M+H)+。
Example I-246-D
(2S, 3S, 4S, 5S)-ethyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) amino) -5- benzene
Base -1- ((R)-piperidines -3- carbonyl) pyrrolidines -2- formic acid esters
Solution of the example I-246-C in trifluoroacetic acid (2mL) is heated to 60 DEG C to continue 1 minute and be concentrated.It will be remaining
Object is in methyl tertiary butyl ether(MTBE) (60mL) and saturation NaHCO3It is distributed between aqueous solution (30mL).These layers are separated and by water layer
It is extracted with methyl tertiary butyl ether(MTBE) (30mL).Combined methyl tert-butyl ether layers are washed with brine, dry (MgSO4), filtering is simultaneously
Concentration is to provide title compound (44mg, 0.076mmol).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm 7.71-7.24
(m, 5H), 7.14 (dd, J=8.5,2.6Hz, 1H), 6.93 (d, J=2.4Hz, 1H), 6.75 (d, J=8.6Hz, 1H), 5.30-
5.22 (m, 1H), 4.53 (d, J=3.0Hz, 1H), 4.14 (qd, J=7.1,2.5Hz, 2H), 3.59-3.46 (m, 5H), 3.36
(d, J=13.5Hz, 1H), 3.15-2.67 (m, 10H), 1.26-1.18 (m, 12H), 1.02 (s, 9H)；LC/MS(ESI+)m/z
578.4(M+H)+。
Example I-246-E
(R)-isopropyl 3- ((2S, 3S, 4S, 5S) -3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) ammonia
Base) -2- (ethoxy carbonyl) -5- Phenylpyrrolidine -1- carbonyl) piperidines -1- formic acid esters
By example I-246-D (44mg, 0.076mmol) and triethylamine (21.23 μ l, 0.152mmol) in CH2Cl2(about
Solution in 0.5mL) is cooled to 0 DEG C, 2M isopropyl chlorocarbonate (49.5 μ l, the 0.099mmol) processing in toluene, in room
Temperature lower stirring 20 minutes, use 37%NH4OH aqueous solution (about 0.5mL) processing, is stirred at room temperature 5 minutes, and in methyl- tert fourth
Base ether (about 30mL) and saturation NaHCO3It is distributed between aqueous solution (about 5mL).Methyl tert-butyl ether layers are washed with brine, it is dry
(MgSO4), it filters, concentration, and carry out chromatography on silica gel, the gradient of 15% to 50% ethyl acetate in heptane
Elution, to provide title compound (43mg, 0.065mmol, 85% yield).1HNMR (400MHz, dimethyl sulfoxide-d6)δppm
7.68-7.53 (m, 2H), 7.38-7.25 (m, 3H), 7.14 (dd, J=8.5,2.5Hz, 1H), 6.94 (d, J=2.2Hz, 1H),
6.75 (d, J=8.5Hz, 1H), 5.80 (bs, 1H), 5.22 (d, J=6.1Hz, 1H), 4.77 (dp, J=21.9,6.2Hz,
2H), 4.55 (d, J=2.7Hz, 1H), 4.14 (q, J=7.0Hz, 2H), 4.01-3.72 (m, 1H), 3.57-3.46 (m, 5H),
3.34 (d, J=13.3Hz, 1H), 1.48-1.35 (m, 2H), 1.31-1.13 (m, 23H), 1.03 (s, 9H)；LC/MS(ESI+)
m/z 664.4(M+H)+。
Example I-246-F
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -
1- [(3R) -1- { [(propane -2- base) oxygroup] carbonyl } piperidines -3- carbonyl] pyrrolidines -2- formic acid
Solution of the example I-246-E (43mg, 0.065mmol) in tetrahydrofuran (1mL) is dilute with methanol (about 1mL)
It releases, is handled with the aqueous NaOH of 1M (about 0.5mL), be heated to 55 DEG C and continue 4 hours, cool down and in the aqueous HCl of 1M (3mL) and acetic acid
It is distributed between ethyl ester (30mL).Ethyl acetate layer is washed with brine, dry (MgSO4), filtering, and is concentrated titled to provide
It closes object (33mg, 0.052mmol, 80% yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.65 (d, J=5.7Hz,
2H), 7.43 (t, J=7.5Hz, 2H), 7.35 (t, J=7.1Hz, 1H), 7.26 (dd, J=8.6,2.3Hz, 1H), 7.09 (d, J
=2.1Hz, 1H), 6.84 (d, J=8.6Hz, 1H), 5.64-5.63 (m, 1H), 5.40 (d, J=7.0Hz, 1H), 4.80
(hept, J=6.2Hz, 1H), 4.57 (d, J=1.8Hz, 1H), 3.98 (d, J=6.3Hz, 1H), 3.92-3.86 (m, 1H),
3.81-3.75 (m, 2H), 3.64 (s, 3H), 3.45 (d, J=13.6Hz, 1H), 2.76-2.65 (m, 3H), 1.52-1.38 (m,
2H), 1.32-1.15 (m, 17H), 1.04 (s, 9H)；LC/MS(ESI+)m/z 636.4(M+H)+。
Example II-341
(2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (cyclohexane carbo) -4- (((2- methoxyl group -5- (3- methoxybenzene
Base) pyridin-3-yl) methyl) amino) -5- Phenylpyrrolidine -2- formic acid
It is filled into 0.5-2.0mL cone bottle from Bai Taiqi company (Biotage), containing conical stirring rod
Enter [1,1 '-bis- (diphenylphosphino) ferrocene] dichloro palladium (II) (PdCl2(dppf), 4.7mg, 10mol%, 0.006mmol).
(2S, 3S, 4S, 5S)-tert-butyl 4- (((bromo- 2- methoxyl group of 5- in anhydrous Isosorbide-5-Nitrae-dioxanes of 1000 μ L is added thereto
Pyridin-3-yl) methyl) amino) -3- (tert-butyl) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid esters (example 25C,
36.0mg, 0.06mmol), 115 μ L contain 2- (3- methoxyphenyl) -4,4,5,5- tetramethyls -1,3,2- bis- dislike penta boron of ring
The 0.6mmol of solution of the alkane (16.1mg, 1.2 equivalents, 0.07mmol) in the anhydrous Isosorbide-5-Nitrae-dioxanes of 1000 μ L is pre-weighed small
The 1M Cs of bottle and 172 μ L2CO3(55.97mg, 3 equivalents, 0.17mmol) aqueous solution.Bottle capping is placed in Biotage
It is heated 30 minutes at 120 DEG C in optimizer.After the completion, by crude mixture in N2Lower drying, and add the trifluoro second of 1000 μ L
Acid.Bottle is covered to juxtaposition again to vibrate at room temperature 1 hour.After the completion, material is passed through into the filter containing 300mg diatomite
Cylinder.Material is washed twice with acetonitrile.By compound in N2Under it is dry in 4mL bottle.Rough material is dissolved in 1400 μ L diformazans
It in base sulfoxide/acetonitrile, and is purified by reversed-phase HPLC, to obtain (2S, 3S, 4S, 5S) -3- (tert-butyl) -1- (hexamethylene carbonyl
Base) -4- (((2- methoxyl group -5- (3- methoxyphenyl) pyridin-3-yl) methyl) amino) -5- Phenylpyrrolidine -2- formic acid
(21.9mg, 49.0% isolated yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 8.26 (d, J=2.4Hz, 1H),
7.60-7.55 (m, 2H), 7.36 (td, J=7.8,2.1Hz, 3H), 7.31-7.26 (m, 1H), 7.08 (d, J=7.7Hz, 1H),
7.04 (t, J=2.1Hz, 1H), 6.93 (dd, J=8.2,2.5Hz, 1H), 5.30 (d, J=7.0Hz, 1H), 4.53 (d, J=
2.1Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.71 (d, J=7.8Hz, 1H), 3.44 (d, J=14.3Hz, 1H),
2.47-2.44 (m, 1H), 1.64 (s, 2H), 1.49 (s, 2H), 1.22 (d, J=12.3Hz, 3H), 1.11-1.03 (m, 3H),
1.02 (s, 1H), 1.00 (s, 9H)；MS(APCI+)m/z 600.1(M+H)+。
Example III-228
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
1- (cyclohexane carbo) -5- (1- methyl -2- oxo -1,2- dihydropyridine -3- base) pyrrolidines -2- formic acid
Example III-228-A
Racemic-(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -1- (cyclohexane carbo) -5- (1- methyl -2- oxygen
Generation -1,2- dihydropyridine -3- base) -4- nitro-pyrrole alkane -2- formic acid esters
By racemic-(2S, 3R, 4S, 5S)-tert-butyl 3- (tert-butyl) -5- (1- methyl -2- oxo -1,2- dihydro pyrrole
Pyridine -3- base) -4- nitro-pyrrole alkane -2- formic acid esters (core 35, chirality enrichment, low ee) pyrrolidines (42mg, 0.11mmol) and three
Ethamine (35 μ L, 0.25mmol) is dissolved in anhydrous methylene chloride (1.0mL), and with cyclohexanecarbonyl chloride (19.5 μ L,
0.15mmol) slowly handle dropwise.Reaction mixture is stirred at room temperature one hour, is then placed directly on silica
Chromatography (100% methyl tertiary butyl ether(MTBE)) is carried out to provide title compound, 45mg (83%).MS(ESI+)m/z 512(M+Na)+。
Example III-228-B
Racemic-(2S, 3S, 4S, 5S)-tert-butyl 4- amino -3- (tert-butyl) -1- (cyclohexane carbo) -5- (1- first
Base -2- oxo -1,2- dihydropyridine -3- base) pyrrolidines -2- formic acid esters
By example III-228-A (44mg, 90 μm of ol) and zinc powder (60mg, 920 μm of ol) in acetic acid (200 μ L) and acetic acid second
It is stirred overnight in ester (700 μ L).More zinc powders (20mg, 310 μm of ol) are added, suspension are stirred at room temperature first, so
Stir about 24 hours at 40 DEG C afterwards.Make reaction mixture to room temperature, diluted with methyl tertiary butyl ether(MTBE), and in thorough methyl- tert
Butyl ether rinses lower by diatomite filtering.Filtrate is placed in progress chromatography (0 to 1% dense NH on plug of silica4OH/
CH3CN) to provide title compound (22mg, 53%).1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.88-
7.67 (m, 1H), 7.56-7.49 (m, 1H), 6.22-6.16 (m, 1H), 5.19-5.12 (m, 1H), 4.30 (d, J=3.4Hz,
1H), 3.73 (dd, J=7.1,3.0Hz, 1H), 3.48 (s, 3H), 2.24-2.05 (m, 1H), 2.01-1.95 (m, 1H), 1.45
(s, 9H), 1.71-1.04 (m, 10H), 0.97 (s, 9H)；MS(ESI)m/z 460(M+H)+.
Example III-228-C
Racemic-(2S, 3S, 4S, 5S)-tert-butyl 3- (tert-butyl) -4- ((5- (tert-butyl) -2- methoxy-benzyl) ammonia
Base) -1- (cyclohexane carbo) -5- (1- methyl -2- oxo -1,2- dihydropyridine -3- base) pyrrolidines -2- formic acid esters
By example III-228-B (21mg, 46 μm of ol), 5- (tert-butyl)-Benzaldehyde,2-methoxy (12mg, 62 μm of ol) and
Zinc chloride (7mg, 0.05mmol) is dissolved in sodium acetate/acetate buffer (pH=4,100 μ L) in methyl alcohol, is used in combination
NaBH3CN (4mg, < 0.07mmol) processing, is then stirred at room temperature one hour.Reaction mixture is concentrated, it is dense with several drops
Aqueous NH4OH processing, uses CH2Cl2/ ethyl acetate/heptane extract and be placed directly on silica carry out chromatography (20% to
100% ethyl acetate/heptane, then 5% methanol/ethyl acetate), to provide the title compound of 22mg (76%).1HNMR
(400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.93-7.66 (m, 1H), 7.58-7.49 (m, 1H), 7.11 (dd, J=
8.5,2.6Hz, 1H), 7.01 (d, J=2.6Hz, 1H), 6.74 (d, J=8.5Hz, 1H), 6.22-6.11 (m, 1H), 5.35-
5.21 (m, 1H), 4.42-4.37 (m, 1H), 3.59 (s, 3H), 3.54-3.42 (m, 5H), 3.38-3.32 (m, 1H), 2.33-
2.05 (m, 2H), 1.73-1.50 (m, 4H), 1.39 (s, 9H), 1.21 (s, 9H), 1.34-1.04 (m, 6H), 0.95 (s, 9H)；
MS(ESI+)m/z 636(M+H)+。
Example III-228-D
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
1- (cyclohexane carbo) -5- (1- methyl -2- oxo -1,2- dihydropyridine -3- base) pyrrolidines -2- formic acid
Example III-228-C (20mg, 31 μm of ol) is dissolved in trifluoroacetic acid (150 μ L), hour is stirred at room temperature, it is dense
Contracting, and be concentrated again from methyl tertiary butyl ether(MTBE), it is subsequently placed under prolonged vacuum, is in two-trifluoroacetic acids with provide 28mg
The title compound of salt.1HNMR (400MHz, dimethyl sulfoxide-d6, 120 DEG C) and δ ppm 7.73-7.60 (m, 2H), 7.25 (dd, J
=8.6,2.6Hz, 1H), 7.16 (d, J=2.6Hz, 1H), 6.84 (d, J=8.6Hz, 1H), 6.29-6.24 (m, 1H), 5.37
(d, J=7.1Hz, 1H), 4.51 (d, J=2.0Hz, 1H), 3.89-3.83 (m, 1H), 3.82-3.78 (m, 1H), 3.70-3.65
(m, 4H), 3.49 (s, 3H), 2.57-2.52 (m, 1H), 2.30 (m, 1H), 1.71-1.52 (m, 4H), 1.48-1.08 (m, "
6H "), 1.24 (s, 9H), 0.96 (s, 9H)；MS(ESI)m/z 580(M+H)+.
Example III-49
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -1- (cyclohexane carbo)-N- ((2- methoxy ethyl) sulphonyl
Base) -4- ((6- methyl -4- (trifluoromethyl) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formamide
It is packed into stirring rod into 4mL bottle, adds racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -1- (hexamethylene carbonyl
Base) -4- ((6- methyl -4- (trifluoromethyl) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formic acid (20.0mg,
0.04mmol) the solution in dichloroethanes and 1,1- carbonyl dimidazoles (CDI, 13.5mg, 2.22 equivalent, 0.08mmol) are two
Solution in chloroethanes.Bottle capping is placed at 42 DEG C and is stirred 4 hours.2- methoxyl group ethyl sulfonamide is added into mixture
The solution and 1 of (15.7mg, 3 equivalents, 0.112mmol) in dichloroethanes, 11 carbon -7- alkene of 8- diazabicylo [5.4.0]
(DBU, 17.0 μ L, 3 equivalents, 0.112mmol), and bottle is covered.Bottle is placed at 50 DEG C and is stirred for 2 hours.After the completion,
Compound is concentrated to dryness, and is re-dissolved in 1400 μ L dimethyl sulfoxides/methanol (1: 1v/v).Mixture is used into reversed-phase HPLC
It is purified, to obtain racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -1- (cyclohexane carbo)-N- ((2- methoxyl group second
Base) sulfonyl) -4- ((6- methyl -4- (trifluoromethyl) pyridine -2- base) amino) -5- Phenylpyrrolidine -2- formamide
(8.3mg, 33.8% isolated yield).1HNMR (400MHz, dimethyl sulfoxide-d6) δ ppm 7.38-7.32 (m, 2H), 7.18
(m, 3H), 6.53 (s, 1H), 6.29 (s, 1H), 5.35 (d, J=8.3Hz, 1H), 5.00 (t, J=8.6Hz, 1H), 4.44 (d, J
=7.2Hz, 1H), 3.80 (t, J=6.3Hz, 2H), 3.63 (dt, J=6.1,2.7Hz, 2H), 3.26 (s, 3H), 2.56-2.53
(m, 1H) 2.37 (s, 3H), 2.28-2.18 (m, 1H), 1.79-1.66 (m, 2H), 1.50-1.41 (m, 2H), 1.20-1.06 (m,
4H), 1.00 (s, 10H), 0.75-0.65 (m, 1H)；MS(APCI+)m/z 653.0(M+H)+。
Table 1.
Table 2.
Table 3.
The determination of bioactivity
Cell surface expression-horseradish peroxidase (CSE-HRP) measurement
People's pulmonary epithelial cell line (CFBE4lo-) (Veit G et al., (2012) Mol Biol Cell. [and molecule with
Cell biology] 23 (21): 4188-4202) in develop with test compound correction (with or without (2 μM of total corrigent
3- [(2R, 4R) -4- ({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl } amino) -
7- methoxyl group -3,4- dihydro -2H- chromene -2- base] benzoic acid)) afterwards for measuring the thin of F508delCFTR cell surface expression
Born of the same parents' measurement.By in the circulation of the 4th outer surface, expression and horseradish peroxidase (HRP) be together for this exploitation
F508delCFTR mutation, and then use from and test correction immunomodulator compounds (not having or have total corrigent) and be incubated for
The luminous reading of overnight these cells CFBE4lo-F508delCFTR-HRP carries out HRP activity measurement to realize.It is first for this
Pacing is fixed, and CFBE4lo-F508delCFTR-HRP cell is connect together with 0.5 μ g/mL Doxycycline with 4,000 cells/wells
Kind is in 384 orifice plates (Greiner Bio-one；Cat 781080) in induce F508delCFTR-HRP to express, and further
At 37 DEG C, 5%CO2It is lower to be incubated for 72 hours.Then test compound (with or without total corrigent) is added with required concentration,
And it is further incubated at 33 DEG C -24 hours 18 hours.The maximum concentration of test is 20 μM, wherein being diluted in using 3 times
8 concentration-response curves in test compound with or without total corrigent.Three repetition plates are run to determine one
A EC50.All plates contain negative control (dimethyl sulfoxide, DMSO) and positive control (2 μM of 3- [(2R, 4R) -4- ({ [1-
(2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl } amino) -7- methoxyl group -3,4- dihydro -2H-
Chromene -2- base] benzoic acid), together with concentration-response on the plate of positive control.After incubation, plate Dulbecco phosphate is delayed
It rushes salt water (DPBS) to wash 5 times, then adds HRP substrate luminol (luminol, 50 μ L), and useMore marks
Remember micropore board detector (Perkinelmer Inc. (Perkin Elmer)；Production number 2104-0010) on shine
Reading measurement HRP activity.It usesAssay Explorer v3.3 analyzes the original count from experiment.
The Z ' that will be greater than 0.5 is used as the qualified standard of plate quality control.
Z ' is defined as:
1-[3*SDPositive control+3*SDNegative control/ absolute value is (averagePositive controlIt is averagePositive control)]
Wherein " SD " is standard deviation.
(will not have or have corrigent (2 μM 3- [(2R, 4R) -4- altogether in test compound using following formula
({ [1- (2,2- bis- fluoro- 1,3- benzodioxole -5- base) cyclopropyl] carbonyl } amino) -7- methoxyl group -3,4- bis-
Hydrogen -2H- chromene -2- base] benzoic acid)) the measurement of each of 8 test concentrations place % activity it is positive right relative to plate
According to being standardized:
% activity (the test compound without total corrigent)=[(the test compound response-without total corrigent
DMSO response)/(positive control response-DMSO response)] * 100
% activity (the test compound with corrigent altogether)=[(test compound response-DMSO with corrigent altogether
Response)/(positive control response-DMSO response)] * 100
Compound (not having or have corrigent altogether) maximum % activity achieved is tested under any test concentrations to exist
It is presented in table 4, while presenting and (being described as using following general sigmoid curves with variable Xi Er slope equation
Model 42 in Assay Explorer v3.3 software) calculated respective EC50:
Y=(a-d)/(1+ (x/c) ^b)+d
With concentration, response, top, bottom, EC50With the general sigmoid curve of Xi Er slope.It can the model describe having
Adjust the sigmoid curve of baseline, a.The equation can be used to matched curve, wherein responding relative to independent variable " x " increasing or decreasing.
" x " is the concentration of tested drug.
" y " is in response to.
" a " is peak response, and " d " is minimum response
" c " is point of inflexion on a curve (EC50).That is, " y " is among lower and upper asymptote as x=c.
" b " is slope factor or hill coefficient.When response increase with the increase of dosage when, the symbol of b be it is positive, when
When response is reduced with the increase of dosage, the symbol of b is negative (inhibition).
Data are provided with qualifier as follows:
Table 4.CSE-HRP data
Data provided in the application show that the compounds of this invention shows activity in vitro, and can in vivo be used in
Treat cystic fibrosis.
By reading present patent application, the other benefit of the invention of applicant for those skilled in the art will be it is aobvious and
It is clear to.
It should be understood that the detailed description of front and the example of accompanying are merely illustrative, and it is not considered as to the present invention
Range limitation, the scope of the invention only limits by the appended claims and its equivalent.To in the common skill in those this fields
For art personnel, various changes and modification to embodiment should be obvious.Without departing from the spirit and scope of the present invention
In the case where, (these change and modification includes but is not limited to: with change for the such change and modification that can carry out purposes of the present invention
Learn those of structure, substituent group, derivative, intermediate, synthesis, preparation or method correlation) or such times for changing and modifying
What is combined.
Claims (21)
1. one kind has the compound or its pharmaceutically acceptable salt of formula (I),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R2AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl and C3-C6Naphthenic base；
R3It is selected from the group, which is made up of: C1-C6Alkyl, C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl；Wherein should
R3C1-C6The substituent group that alkyl is optionally independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkane
Oxygroup, OH, oxo, CN, NO2, F, Cl, Br and I；The wherein R3C3-C6Naphthenic base, phenyl and 5-6 unit's heteroaryl are optionally
The substituent group for being independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-
C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；And
R3AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R3And R3AC is formed together with the carbon attached by them3-C6Naphthenic base；Wherein by R3And R3AAnd the carbon shape attached by them
At the C3-C6The substituent group that naphthenic base is optionally independently selected by one or more from the following group replaces, which is made up of:
C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2, F, Cl, Br and I；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring base, L1-
C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base, C3-
C11Naphthenic base and C4-C11Cycloalkenyl be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2、F、
Cl, Br and I；Wherein L1It is not present, or is selected from the group, which is made up of: C1-C6Alkylidene, C2-C6Alkenylene, C2-C6It is sub-
Alkynyl and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene and C2-C6Alkynylene, individually or
As a part of group, the substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of:
C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、
NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, the 4-6 member list condensed with phenyl group
Ring heterocycle, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl and phenyl base
The condensed 4-6 unit monocycle heterocycle of group, C3-C11Naphthenic base and C4-C11Cycloalkenyl is optionally independently selected by one or more from
The substituent group of the following group replaces, which is made up of: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 member are miscellaneous
Aryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl and
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, the group
It is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、F、Cl、Br
And I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-
10 yuan of aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6
Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, the group
It is made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23, OH, oxo, CN,
NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and
The substituent group that 4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of: R24、
OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl and 5-6
Unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2、F、
Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkene
Base, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；
Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alcoxyl
Base, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of；C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-1l unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I；
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkane
Oxygroup-C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Ring
Alkenyl and 4-12 circle heterocyclic ring base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein
R2It is C (O) OH；And
R2AIt is hydrogen.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein
R2It is-C (O) NHSO2RG3aOr-C (O) NHSO2N(RG3a)2；
RG3aIt is independently C at each occurrence1-C6Alkyl, C1-C6Alkyl-O-C1-C6Alkyl or GA；
GAIndependently naphthenic base at each occurrence, the naphthenic base be independently unsubstituted or by 1,2 or 3 independently
The R of selectionuWhat group replaced；
RuIt is independently C at each occurrence1-C6Alkyl；And
R2AIt is hydrogen.
4. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein
R5It is phenyl；The wherein R5Phenyl is unsubstituted.
5. one kind has the compound or its pharmaceutically acceptable salt of formula (III),
Wherein
R1It is selected from the group, which is made up of: SO2R6、C(O)R6、C(O)OR6With C (O) NR7R8；
R2It is C (O) OH or its bioisostere；
R4It is selected from the group, which is made up of: L1-C6-C10Aryl, L1- 5-11 unit's heteroaryl, L1- 4-12 circle heterocyclic ring base, L1-
C3-C11Naphthenic base and L1-C4-C11Cycloalkenyl；The wherein R4C6-C10Aryl, 5-11 unit's heteroaryl, 4-12 circle heterocyclic ring base, C3-
C11Naphthenic base and C4-C11Cycloalkenyl be optionally independently selected by one or more from the following group substituent group replace, the group by with
Lower composition: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2、F、
Cl, Br and I；Wherein L1It is not present, or is selected from the group, which is made up of: C1-C6Alkylidene, C2-C6Alkenylene, C2-C6It is sub-
Alkynyl and C1-C6Alkylidene-O-；The wherein L1C1-C6Alkylidene, C2-C6Alkenylene and C2-C6Alkynylene, individually or
As a part of group, the substituent group for being optionally independently selected by one or more from the following group replaces, which is made up of:
C1-C6Alkoxy, OH and oxo；And
R4AIt is selected from the group, which is made up of: hydrogen, C1-C6Alkyl and C1-C6Halogenated alkyl；Or
R4And R4A4-12 circle heterocyclic ring base is formed together with the carbon attached by them；Wherein the 4-12 circle heterocyclic ring base is optionally by one
Or multiple substituent groups independently selected from the group below replace, which is made up of: R9、OR9、C(O)OR9、C(O)NR10R11、SR9、
NR10R11、Si(R9)3、SF5、SO2R9, OH, oxo, CN, NO2, F, Cl, Br and I；
R5It is selected from the group, which is made up of: C6-C10First aryl, 5-11 unit's heteroaryl, the 4-6 member list condensed with phenyl group
Ring heterocycle, C3-C11Naphthenic base and C4-C11Cycloalkenyl；The wherein R5C6-C10First aryl, 5-11 unit's heteroaryl and phenyl base
The condensed 4-6 unit monocycle heterocycle of group, C3-C11Naphthenic base and C4-C11Cycloalkenyl is optionally independently selected by one or more from
The substituent group of the following group replaces, which is made up of: R12、OR12、NR13R14, OH, oxo, CN, NO2, F, Cl, Br and I；
R6It is selected from the group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 member are miscellaneous
Aryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；The wherein R6C1-C6Alkyl, C2-C6Alkenyl and
C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, which is made up of: R15、OR15、
SR15、NR16R17、OH、CN、NO2, F, Cl, Br and I；The wherein R66-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base,
C4-C11The substituent group that cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, the group
It is made up of: R18、OR18、C(O)R18、OC(O)R18、C(O)OR18、SO2R18、NR19R20, OH, oxo, CN, NO2、F、Cl、Br
And I；
R7And R8It is hydrogen or C each independently1-C6Alkyl；
R9At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-
10 yuan of aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R9C1-C6
Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group replaces, the group
It is made up of: R21、OR21、C(O)R21、OC(O)R21、C(O)OR21、C(O)NR22R23、SO2R21、NR22R23, OH, oxo, CN,
NO2, F, Cl, Br and I；Wherein each R96-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and
The substituent group that 4-12 circle heterocyclic ring base is optionally independently selected by one or more from the following group replaces, which is made up of: R24、
OR24、C(O)R24、OC(O)R24、C(O)OR24、SO2R24、NR25R26, OH, oxo, CN, NO2, F, Cl, Br and I；
R10And R11At each occurrence independently selected from the following group, which is made up of: hydrogen, C1-C6Alkyl, phenyl and 5-6
Unit's heteroaryl；Wherein each R10And R11Phenyl and 5-6 unit's heteroaryl are optionally independently selected by one or more from taking for the following group
Replace for base, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, OH, oxo, CN, NO2、F、
Cl, Br and I；
R12At each occurrence independently selected from the following group, which is made up of；C1-C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkene
Base, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；
Wherein each R126-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are appointed
The substituent group that selection of land is independently selected by one or more from the following group replaces, which is made up of: C1-C6Alkyl, C1-C6Alcoxyl
Base, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy, N (C1-C6Alkyl)2, OH, oxo, CN, NO2, F, Cl, Br and I；
R13And R14It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R15C1-C6Alkyl, C2-C6Alkenyl and C2-C6The substituent group that alkynyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: OH, oxo, CN, NO2, F, Cl, Br and I；Wherein each R156-10 member aryl, 5-11 member heteroaryl
Base, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group
Substituent group replaces, which is made up of: C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, oxo, OH, CN, NO2、F、
Cl, Br and I；
R16And R17It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R18At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R18C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C6-C10First aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: C1-C6Alkyl, C1-C6Alkoxy, 5-6 unit's heteroaryl, OH, oxo, CN, NO2, F, Cl, Br and I；
R19And R20It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R21At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；It is wherein each
R21C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cyclenes
The substituent group that base and 4-12 circle heterocyclic ring base are optionally independently selected by one or more from the following group replaces, and the group is by with the following group
At: OH, oxo, CN, NO2, F, Cl, Br and I:
R22And R23It is hydrogen or C each independently at each occurrence1-C6Alkyl；
R24At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkane
Oxygroup-C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Ring
Alkenyl and 4-12 circle heterocyclic ring base；And
R25And R26It is hydrogen or C each independently at each occurrence1-C6Alkyl.
6. compound as claimed in claim 5 or its pharmaceutically acceptable salt, wherein
R1It is C (O) OR6；
R6It is C1-C6Alkyl；The wherein R6C1-C6The substituent group that alkyl is optionally independently selected by one or more from the following group takes
Generation, the group are made up of: R15、OR15、SR15, OH and F；And
R15At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl,
6-10 member aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base；Wherein each R156-
10 yuan of aryl, 5-11 unit's heteroaryl, C3-C11Naphthenic base, C4-C11Cycloalkenyl and 4-12 circle heterocyclic ring base optionally by one or
Multiple substituent groups independently selected from the group below replace, which is made up of: C1-C6Alkyl, OH, CN, F and Cl.
7. compound as claimed in claim 5 or its pharmaceutically acceptable salt, wherein
R5It is phenyl；The wherein R5Phenyl is unsubstituted.
8. compound as claimed in claim 5 or its pharmaceutically acceptable salt, wherein
R5It is pyridyl group；The wherein R5The substituent group that pyridyl group is optionally independently selected by one or more from the following group replaces, the group
It is made up of: R12、OR12、NR13R14, F, Cl and Br；
R12At each occurrence independently selected from the following group, which is made up of: C1-C6Alkyl, C1-C6Halogenated alkyl, C3-C11
Naphthenic base and 4-12 circle heterocyclic ring base；And
R13And R14It is C each independently at each occurrence1-C6Alkyl.
9. compound as described in claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from by following
The group of composition:
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -
2- yl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methoxyl group -4- (trifluoromethyl) pyrrole
Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- [(2S) -
Oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- [(2R*) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (difluoro-methoxy) phenyl] -4- ({ [2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (benzenesulfonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(oxane -2-
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(2S*, 3S*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyl group -5- phenylpyridine -3- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -2,
3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S) -3,3-
Difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -3,3-
Difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -2- first
Oxygroup -3- phenylpropionyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl
Base] phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S)-oxygen penta
Ring -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cis- -4- hydroxyl
Base -4- propyl cyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -2,
3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethyl
Amino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] pyrrolidines -2-
Formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3- (2-
Methoxy propane -2- base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -5- [2-
(dimethylamino) pyridin-3-yl] -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R*) -3,
3- difluorocyclohex alkane -1- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -3,
4- dihydro -2H-1- chromene -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S*) -3,
3- difluorocyclohex alkane -1- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (difluoro first
Oxygroup) phenyl] -1- [(2R)-oxane -2- carbonyl] pyrazole, pyrrole alkane -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyl group
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trimethyl silyl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -5- methoxypyridine -4- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorobenzene
Base) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (2,
2,6,6- tetramethyl oxane -4- carbonyls) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(5- tert-butyl -2- methoxypyridine -3- base) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- hydroxyl -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base)-N- (mesyl) -5- Phenylpyrrolidine -2- formamide；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (difluoro first
Oxygroup) phenyl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (1- first
Tetramethylcyclobutyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(propane -2-
Base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
[(2S*)-is disliked (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
Alkane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [4- (3- chlorphenyl) oxane -4- base] methyl } amino) -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -4- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(6- tert-butyl -2- methoxypyridine -3- base) first
Base] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -5- [2- (dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S*, 2R*,
4R*) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -5- (2- methoxypyridine -3- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (1- first
Tetramethylcyclobutyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -1- { [(propane -
2- yl) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
[(2R)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (3- chlorobenzene
Base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] first
Base } amino) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -5- (2-
Aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- ring
Propyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- first
Base phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- cyclopropyl
Pyridin-3-yl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (ethoxy carbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (Cyclopentanecarbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(5- tert-butyl -2-
Methoxyphenyl) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- [(2S)-butyl oxide link -
2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- { [(5- tert-butyl -2-
Methoxyphenyl) methyl] amino } -1- (cyclobutanecarbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- chlorphenyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl]
Amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S)-oxygen penta
Ring -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) first
Base] amino } -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl]
Amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- ring
Propyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- cyclopropyl
Phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -5-
(2- aminomethyl phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methylbenzene
Base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- second
Base phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) benzene
Base] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2,2- dimethyl -2,3- dihydro -1- benzofurans -
7- yl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] (methyl) amino } -
1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [(4,6- dimethoxypyridin -2- base) ammonia
Base] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(4- chloro-6-methoxylpyrimidin -2- base) amino] -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [1- (2,2- bis- fluoro- 2H-1,3- benzo
Dioxole -5- base) ethyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- methoxyl group -1,3- dimethyl -1H-
Pyrazoles _ 4- yl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [4- (trifluoromethyl) pyrimidine -
2- yl] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- cyclopropyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -
2- yl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ 1- [2- methoxyl group -5- (trifluoromethyl)
Phenyl] ethyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(2,6- dimethoxypyridin -4- base) ammonia
Base] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methoxyl group -4- (trifluoromethyl) pyridine -2- base] amino } -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) phenyl] first
Base } amino) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [4- methyl -6- (trifluoromethyl) pyrimidine -2-base] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) -5- methoxyl group
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) phenyl] first
Base } amino) -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(4R, 6R, 7R) -5- (cyclohexane carbo) -7- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -
6- phenyl -5- azaspiro [2.4] heptane -4- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -5- (6- first
Oxygroup pyridine -2- base) -1- (oxane -2- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (6- methoxypyridine -2- base) -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- (difluoro-methoxy) pyridine -2- base]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) phenyl] -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -1- [oxane -2- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -1- (3- oxabicyclo [3.1.0] hexane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -1- [oxane -2- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [(2,2- dimethyl oxanes -
4- carbonyl] -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(3R) -1- (methoxycarbonyl) piperidines -3- carbonyl] -4- { [6- first
Base -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (mesyl) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4- { [6- first
Base -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
1- [(2S*) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
(2R*, 3R*, 4R*, 5R*) -3- tert-butyl-l- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (propane -2- base) benzene
Base] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxypyridine -3- base of 5-) methyl] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- benzene
Base -1- (spiral shell [2.5] octane -6- carbonyl) coughs up alkane -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- { [6- methoxyl group -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (3-Methoxy Pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (2- methoxyl group -2- methylpropionyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) _ 4- { [(3- methoxynaphthalene -2- base) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (difluoro-methoxy) phenyl] -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2-
Methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(1- benzofuran -2- base) methyl] amino } -3- tert-butyl -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,3- dihydros-Isosorbide-5-Nitrae-benzo dioxin -6- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (cyclo propyl methoxy) -4- fluorophenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- chlorine-2-hydroxyl phenyl) methyl] amino } -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [6- (propane -2- base) -4- (fluoroform
Base) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(3- cyano -4- methoxy quinoline -2- base) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- [3- (trifluoromethyl) anilino-] pyrroles
Alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (cyclohexane carbo) -
5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S, 3S) -
3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S, 3S) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3- (2-
Methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3- (2-
Methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (pyrrole
Pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- benzoyl -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,1- dioxy
- 1 λ of generation6Vulcanize pentamethylene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [6- cyclobutyl -4- (trifluoromethyl) pyridine -2- base] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- benzyl -2- methoxypyridine -3- base) methyl] amino } -3- tert-butyl -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (butane -2- base) -2- methoxypyridine -3- base] methyl } amino) -3- tert-butyl -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxypyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxypyridine -3- base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxypyridine -3- base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2- ethyl-butyl) -2- methoxypyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- phenylethyl) pyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methyl-propyl) pyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 5- [(3- cyano-phenyl) methyl] -2- methoxypyridine -3- base } methyl)
Amino] -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base) methyl] amino } -1- [(1R,
3R) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- hydroxy phenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (5- tert-butyl -2- methoxybenzene amido) -1- (cyclohexane carbo) -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -3,
4- dihydro -2H-1- chromene -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1- [(is disliked
Alkane -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 5- [(dimethylamino) methyl] -2- methoxyl group
Phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (five fluoro- λ6Sulfanyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base) methyl] amino } -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (2- dicyanopropane -2- base) -2- methoxyphenyl] methyl } amino) -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- (2- hydroxy propane -2- base) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (5- cyano -2-
Methoxybenzoyl base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1,3- bis-
Hydrogen -2H- iso-indoles -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(sulphur benzene -3- base) acetyl group] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- fluorine quinoline -
2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methyl-propyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -2-
Cyclopropyl -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -2-
Cyclopropyl -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [(1S, 3s)-tricyclic
[3.3.1.13,7] decane -1- base] phenyl methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1H- imidazoles -
4- yl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- hydroxyl ring
Amyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- [(azepan -1- base) acetyl group] -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyl group
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- ethyl -4-
Oxo-Isosorbide-5-Nitrae-dihydropyridine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- methyl -
4H- furans simultaneously [3,2-b] pyrroles -5- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
[(4- is chloro- by 2- by -1- by (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino }
1H- pyrazol-1-yl) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(2R*, 3R*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- [(2R*, 3R*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- [(2S*, 3S*) -3- (propane -2- base) butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3aR*,
6aS*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(3aR*, 6aS*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- ({ [2- methoxyl group -5- (propane -
2- yl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5- (propane -
2- yl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (4- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methoxy propane -2- base)
Pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyrimidine -5- base) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (cyclohexane carbo) -
3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxypyridine -3- base) methyl] amino } -
3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxyphenyl] methyl } amino) -1- (ring
Hexane carbonyl) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxyphenyl] methyl } amino) -
3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(cyclopenta oxygen
Base) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2-
Methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyrrolidin-1-yl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (piperidin-1-yl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2. methoxyl group -5- (pyridazine -4- base) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 '-fluoro- 4- methoxyl group [1,1 '-biphenyl] -3-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,4- dimethyl -1,3-thiazoles -5- base) -
2- methoxyphenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 '-cyano -4- methoxyl groups [1,1 '-biphenyl] -3- base) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (3,6- dihydro -2H- pyrans -4- base) -2- first
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (4- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxypyridine -3- base) first
Base] amino } -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxypyridine -3- base] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 3-Methoxy Pyridine -2- base of 6-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -3-
(1- methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -2- benzene
Oxygroup propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (methylsulfonyl
Base) piperidines -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(trans-) -2- (pyridin-3-yl) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2- fluorophenyl) -2- methoxypyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl } methyl) ammonia
Base] -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (pyrrole
Azoles simultaneously [1,5-a] pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [5- ethyl -1-
(6- methoxyl group pyridazine -3- base) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- tert-butyl -
5- (propane -2- base) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (2- fluorobenzene
Base) -3,5- dimethyl -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,5- diformazan
Base -2,3- dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- hydroxyl ring
Butyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- [2- (azetidine -1- carbonyl) hexamethylene -1- carbonyl] -3- tert-butyl -4- { [(tertiary fourth of 5-
Base -2- methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [cis- -4- hydroxyl
Base -4- (propyl- 2- alkene -1- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cis- -4- second
Base -4- hydroxycyclohexan -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [cis- -4- hydroxyl
Base -4- (propane -2- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (phenoxy group carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(2- chlorobenzene
Base) methoxyl group] carbonyl } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (1- cyano cyclobutyl) -2- methoxyphenyl] methyl } amino) -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 2, the 3- dihydro -1H- indenes -2- base of 4-) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 2, the 3- dihydro -1H- indenes -2- base of 5-) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 2, the 3- dihydro -1H- indenes -1- base of 5-) amino] -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -2-
(3,4- difluorophenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [cyclohexyl (first
Oxygroup) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -3- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- [3- (trifluoromethyl) pentamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (5,5- dimethyl butyl oxide link -2- carbonyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -2,
3- dihydro -1- benzofuran -2- carbonyl] -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -2,
3- dihydro -1- benzofuran -2- carbonyl] -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -2,3-
Dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- cyclobutyl -5- methoxypyridine -4- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- cyclopenta -5- methoxypyridine -4- base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 3- methoxyl group -6- [1- (trifluoromethyl) cyclopropyl
Base] pyridine -2- base } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trimethyl silyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- oxa- two
Ring [3.2.1] octane -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl }
Amino) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethyl
Amino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [1- (trifluoromethyl) cyclopropyl] phenyl } methyl) amino] pyrrolidines -2-
Formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [1- (three
Methyl fluoride) cyclopropyl] phenyl } methyl) amino] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (is disliked
Alkane -2- carbonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(2R*, 3R*) -3- phenyl butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(2S*, 3S*) -3- phenyl butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (3,3-
Difluorocyclohex alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- phenyl -
1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) _ 4- ({ [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [(trifluoromethyl) sulfanyl]
Phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -3- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyl group
Phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) _ 4- { [(2- methoxynaphthalene -1- base) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -5- (three
Methyl silicane base) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -4- { [(6- methoxyl group -2,3-
Dihydro -1H- indenes -5- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3S*) -1-
Methyl -2- oxo-piperidine -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,1- dioxy
- 1 λ 6- Thiophane -2- carbonyl of generation) -5- Phenylpyrrolidine -2- formic acid；
[(2S*)-is disliked (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
Alkane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { (2S*) -2-
[(2S*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { (2R*) -2-
[(2R*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (3- first
Oxygroup hexamethylene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*, 3S*) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3- dihydros -
Isosorbide-5-Nitrae-benzo dioxin -6- carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [4- (cyclohexyl
Oxygroup) benzoyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyl group
Phenyl) methyl] amino } -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base)-N- (mesyl) -5- Phenylpyrrolidine -2- formamide；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(1R*, 2R*, 3R*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl
Base] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S*) -2,3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (3,4-
Dihydro -1H-2- chromene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -4- methoxy pyrimidine -5- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (ring
Hexane carbonyl) -2- methyl -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- methoxyl group -2- (pyrrolidin-1-yl) pyridine -
4- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1,1,1- tri- fluoro- 2- methyl
Propane -2- base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
[(2R*)-is disliked (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
Alkane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [2-
(propane -2- base) butyl oxide link -3- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [4- (2- chlorphenyl) oxane -4- base] methyl } amino) -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethylamino) pyrrole
Pyridine -3- base] -3- (2- methoxy propane -2- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorobenzene
Base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -5- [2- (dimethylamino) pyridine -
3- yl] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (difluoro first
Oxygroup) phenyl] -1- [(1S*, 2S*, 3S*, 4R*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrole
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -5- (2- methoxypyridine -3- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- [2- (difluoro-methoxy) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (difluoro first
Oxygroup) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- (cyclohexane carbo) -5- [2- (difluoro-methoxy) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- [2- (difluoro-methoxy) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- fluorine
Phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (tert-butoxycarbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl]
Amino } -5- (2- methoxypyridine -3- base) coughs up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- first
Oxygroup pyridin-3-yl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) first
Base] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl]
Methyl } amino) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S*, 2R*,
4R*) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxyl group
Pyridin-3-yl) methyl] amino } -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(oxa- ring
Butane -3- base) oxygroup] carbonyl } -5- Phenylpyrrolidine -2- formic acid；
({ [(five is fluoro- by 2- methoxyl group -5- by -4- by (2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl]
λ6Sulfanyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(3R) -1- { [(propane -2- base) oxygroup] carbonyl } piperidines -3- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- chloropyridine -3- base) methyl] amino } -1- [(1R) -3,
3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- (1- cyclo-propane -1- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- { [(propane -2- base)
Oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(3- methoxyl group -5,5,8,8-
Tetramethyl -5,6,7,8- naphthane -2- bases) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (3- chlorphenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl }
Amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- [(2S) -2- Phenylbutanoyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(7R) -2,2-
Two fluoro- 7- methyl -6,7- dihydro -2H- furans simultaneously [2,3-f] [1,3] benzodioxole -7- carbonyl] -5- (2- first
Oxygroup pyridin-3-yl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- (2- methoxypyridine -3-
Base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- (2- methoxypyridine -3-
Base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- phenyl -
1- [(1R*, 3S*) -3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- phenyl -
1- [(1S*, 3R*) -3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methylbenzene
Base) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5-
(2- aminomethyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -4- [(2- phenylethyl) amino] -1- { [(propane -2- base) oxygroup] carbonyl
Base } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(2- methyl -2- phenyl propyl) amino] -5- phenyl -1- { [(propane -2- base)
Oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- first
Base phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- first
Base phenyl) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [4- (2- methoxyphenyl) oxane -4- base] methyl } amino) -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- [({ 1- [4- (fluoroform
Base) phenyl] piperidines -3- base } methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl pyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) benzene
Base] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
[relative configuration-(1R, 2S, 4S) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrroles
Alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclopropane carbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [1.1.1] pentane -1- carbonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -4- { [(the bromo- 2- ethoxyl phenenyl of 5-) first
Base] amino } -3- tert-butyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl phenyl) -4- ({ 3- [(2- methoxypyridine -3- base) amino] ring
Butyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclobutane carbonyl
Base) -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) first
Base] amino } -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl]
Methyl } amino) -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclobutanecarbonyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- chlorphenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl]
Methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (1- first
Tetramethylcyclobutyl) phenyl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- hydroxy phenyl) methyl] amino } -1- [(2S)-oxygen penta
Ring -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (trifluoromethyl) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -5- (2- methylbenzene
Base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl]
Methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrazole, pyrrole alkane -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl }
Amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl }
Amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl]
Amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl]
Methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) methyl]
Amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- (2- bromophenyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] first
Base } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- ring
Propyl phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- second
Base phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2,3-
Dihydro -1- benzofuran -7- base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2,3- dihydro -1- benzofuran -7- base) -4- [(3- methoxyl group -5,6,7,
8- naphthane -2- base) methyl] amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (6- first
Oxygroup pyridine-2-sulfuryl base) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -1-
[(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2,2- dimethyl -2,3- dihydro -1- benzofuran -7- base) methyl] ammonia
Base } -1- [(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2,2- dimethyl -2,3- dihydro -1- benzofuran -7- base) methyl] ammonia
Base } -1- [(2S)-oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2,2- dimethyl -2,3- dihydro -1- benzofuran -7- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- (chloro- 7- methoxyl group -1, the 3- dihydro -2H- iso-indoles -2- base of 4-) -1- [(2S) -
Oxane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ 2- [2- methoxyl group -5- (trifluoromethyl) phenoxy group] ethyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- hydroxy phenyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(5- chloropyridine -2- base) amino] -1- (cyclohexane carbo) -5- benzene
Base pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- chloro- 4- (trifluoromethyl) pyridine -2- base] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 4- Dimethoxyphenyl of 3-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- [({ 2- [(propane -2- base) oxygen
Base] phenyl } methyl) amino] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- methyl propoxyl group) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxypyridine -3- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 3-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [5- chloro- 2- (difluoro-methoxy) phenyl] methyl } amino) -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- chloro-2-ethoxy phenyl) methyl] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 6- methoxyphenyl of 2-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -1- [two (propane -2- base) carbamoyls] -3- methyl -4- { [6- methyl -4- (trifluoromethyl)
Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (cyclohexane carbo) -3-
Cyclopropyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- chloro- 5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- chloro- 5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -
1- (cyclohexane carbo) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) -4- methoxyl group
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -1- [oxane -2- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -1- [oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -1- [oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2- (two
Methylamino) phenyl] -1- [oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [2,2- dimethyl oxane -4-
Carbonyl] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (two
Methylamino) phenyl] -1- [2,2- dimethyl oxane -4- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2- (two
Methylamino) phenyl] -1- [2,2- dimethyl oxane -4- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(3S) -1- (methoxycarbonyl) piperidines -3- carbonyl] -4- { [6- first
Base -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 2- methoxypyridine -3- base of 5-)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (trifluoromethyl) benzene
Base] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
5- phenyl -1- (phenyl acetyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2- methoxy
Base -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
1- [(2R, 3R) -2- methyl oxane -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
1- [(2S, 3S) -2- methyl oxane -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- ((2- methoxyl group -5- (trifluoromethyl) benzyl) amino) -1-
((1R, 3R) -3- methoxycyclohexyl alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- ((2- methoxyl group -4- (trifluoromethyl) benzyl) amino) -1-
((1R, 3R) -3- methoxycyclohexyl alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- (tert-butyl) -4- ((the chloro- 2- methoxy-benzyl of 4-) amino) -1- ((1R, 3R) -3-
Methoxycyclohexyl alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the fluoro- 2- methoxyphenyl of 4-) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- methoxyl group -5- aminomethyl phenyl) methyl] amino } -5- phenyl -
{ 1. [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethoxy) phenyl] methyl } ammonia
Base) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the fluoro- 2- methoxyphenyl of 5-) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- benzene
Base -1- { [(- 2. base of propane) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (propane -2- base) phenyl] methyl } amino) -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- methoxyphenyl) methyl] amino } -5- phenyl -1- { [(third
Alkane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -5- [2- (two
Methylamino) pyridin-3-yl] -1- [(2R) -2- methoxyl group -2- phenyl acetyl] pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2- methoxy
Base -2- phenyl acetyl] -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -
1- ((2S)-oxane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -
4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -
4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methyl -4- (trifluoromethyl) pyridine -
2- yl] amino } -5- (pyridine -2- base) pyrrolidines -2- formic acid；
(2S*, 3S*, 4S*, 5S*) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- [(2R) -2- first
Oxygroup -2- phenyl acetyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- benzene
Base -1- (phenyl acetyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -
1- [(2S*) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
1- (butyl oxide link -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -
1- (butyl oxide link -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (oxygen penta
Ring -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [(2R) -2- methoxyl group -2- phenylacetyl
Base] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (dimethylamino
Base) phenyl] -1- [(2R) -2- methoxyl group -2- phenyl acetyl] pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
1- [(2R) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -
1- [(2R*) -2- phenoxy group propiono] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (4,4- difluorocyclohex alkane -1- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (4,4- difluorocyclohex alkane -1- carbonyl) -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -
5- phenyl -1- (spiral shell [2.5] octane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- cyano -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methyl -5- (trifluoromethyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (propane -2- base)
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(4- cyano -2- methoxyphenyl) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [5- chloro- 2- (trifluoromethoxy) phenyl] methyl } amino) -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (trifluoromethoxy) benzene
Base] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -6- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -
5- phenyl -1- [(2S*) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- [(2R) -
Oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- [(2S) -
Oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -5- (2- methoxypyridine -3-
Base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Isosorbide-5-Nitrae-dioxanes -2- carbonyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (Isosorbide-5-Nitrae-two
Oxane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2- methoxyl group -2- benzene
Base acetyl group] -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -
4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- { [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
[(cyclobutyl oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (cyclohexane carbo) -
5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) benzene
Base] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] first
Base } amino) -5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (cyclohexane carbo) -
5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (cyclohexane carbo) -
5- (2- picoline -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) benzene
Base] methyl } amino) -1- [(2R*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(1- benzofuran -3- base) methyl] amino } -3- tert-butyl-l- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- Chloro-2-fluoro-5-methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,5- dichlorophenyl) methyl] amino } -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 5- methoxyphenyl of 2-) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- chloro- 2- (difluoro-methoxy) phenyl] methyl } amino) -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [3,5- bis- (trifluoromethyl) phenyl] methyl } amino) -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- methoxyl group -2- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 5- methoxyphenyl of 2-) methyl] amino } -3- tert-butyl -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- dichlorophenyl) methyl] amino } -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 3- methoxyphenyl of 4-) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,4- dichlorophenyl) methyl] amino } -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the fluoro- 5- methoxyphenyl of the bromo- 4- of 2-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- difluorophenyl) methyl] amino } -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(dioxane between 6- methoxyl group -2H-1,3- benzo
Amylene -5- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,5- 3,5-dimethylphenyl) methyl] amino } -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 2- methoxyphenyl of 4-) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- ethyoxyl -2- aminomethyl phenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxy-propio] -4- ({ [2- methoxyl group -5- (trifluoromethyl)
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- tert-butyl-phenyl) methyl] amino } -1- (cyclohexane carbo) -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [3- (trifluoromethyl) phenyl] methyl }
Amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- methoxyl group -4- aminomethyl phenyl) methyl] amino } -5- (2- methoxyl group pyrrole
Pyridine -3- base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- [2- (difluoro-methoxy) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3- methoxyl group -5,6,7,8- naphthane -2- bases)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- ethoxyl phenenyl of 5-) methyl] amino } -3- tert-butyl -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- methoxyl group -3- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4,5- difluoro-2-methoxy base) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- ethyoxyl -2,3- dihydro -1H- indenes -5- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(the fluoro- 3- Phenoxyphenyl of 4-) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,4- 3,5-dimethylphenyl) methyl] amino } -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- 3,5-dimethylphenyl) methyl] amino } -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- di-t-butyl phenyl) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxyphenyl) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] first
Base } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxyphenyl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- (2- methoxybenzene
Base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyl group -4- aminomethyl phenyl) methyl] ammonia
Base } -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- chloro- 2- (cyclo propyl methoxy) phenyl] methyl } amino) -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (2- methoxypyridine -3- base) coughs up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the fluoro- 4- methylquinoline -3- base of the chloro- 6- of 2-) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 5- cyanopyridine -3- base of 2-) amino] -1- (cyclohexane carbo) -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(3- cyano -6- picoline -2- base) amino] -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [3- cyano -4- (methoxy) -6- picoline -2- base] amino } -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- [3,5- bis- (trifluoromethyl) anilino-s] -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl pyrazoline
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R, 3R) -
3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- benzoyl -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,1- dioxy
- 1 λ of generation6Vulcanize pentamethylene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- methyl -
1H- pyrazoles -3- sulfonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (benzenesulfonyl) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl }
Amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (2,3- dihydros-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl) -4- ({ [2- methoxyl group -
5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (propane -2- base) pyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [(2R) -3- methoxyl group -2- first
Base -3- oxopropyl] pyridin-3-yl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- methoxyl group [1,1 '-biphenyl] -3- base) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- [(2- first
Base propoxyl group) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(oxane -4-
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,4- dihydro -2H-1- chromene -2- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -3,
4- dihydro -2H-1- chromene -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4- dihydros -
1H-2- chromene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [2- (propane -2- base) phenyl] methyl }
Amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(chloro- 3, the 4- dihydro -2H-1- chromene -4- base of 6-) amino] -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (propane -2- base) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (propane -2- base) phenyl] methyl } amino) -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -3- tert-butyl -5- phenyl -1- { [(third
Alkane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- ethyl -
2- Methyl-1H-indole -3- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S, 2R,
4R) -4- (2- cyano ethyl) -2- methyl cyclopentane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (dislike by 4- methyl
Alkane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- cyano ring
Hexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(6,6- diformazans
Base oxane -3- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- [(two rings [1.1.1] pentane -1- base) acetyl group] -3- tert-butyl -4- { [(5- tert-butyl -2-
Methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -3,
4- dihydro -1H-2- chromene -1- base] acetyl group } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(oxane -3-
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (benzene
Base acetyl group) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- fluorobenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(sulphur benzene -2- base) acetyl group] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- chlorobenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(pyridin-3-yl) acetyl group] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (1- benzofuran -3- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [3-
(trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(pyrrolidin-1-yl) acetyl group] pyrazole, pyrrole alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4,4- difluoros
Cyclohexyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [1-
(pyridine -2- base) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethoxy) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- benzyl -2- methoxyphenyl) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- hydroxy benzenes
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- hydroxy benzenes
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,6- diformazans
Yl pyridines -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- methyl pyrrole
Pyridine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- fluorobenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,5- difluoros
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,6- difluoros
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,5- difluoros
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- methylbenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- methylbenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- methylbenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- fluorobenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- methoxyl group -
1- methyl-1 H- pyrazoles -5- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl _ 4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,5- diformazans
Base sulphur benzene -3- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(morpholine -4-
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1- hydroxyl ring
Hexyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [2.2.1] hept- 5- alkene -2- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxy
Base phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(hexamethylene -2-
Alkene -1- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,4- bis-
Hydrogen -2H-1- chromene -4- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- methoxyl group
Hexamethylene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (2-
Phenylpropionyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [2-
(propane -2- base) -1,3- dioxanes -5- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- oxo -
2,3- dihydro -1H- indenes -1- bases) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,3- difluoros
Cyclopenta) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,2- difluoros
Cyclopenta) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,3- bis-
Fluoro- 1- methylcyclopentyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- methyl -
4- oxo -3,4- dihydro phthalazines -1- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3- dihydros -
1- benzofuran -7- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [chloro- 6- oxygen of 5-
Generation -1- (propane -2- base) -1,6- dihydropyridine -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- { 4-
[(pyridine -2- base) oxygroup] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- { 3-
[(1H-1,2,4- triazol-1-yls) methyl] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- methyl -3-
Phenyl -1H- pyrazoles -5- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- methyl -5-
Phenyl -1H- pyrazoles -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S)-3- tert-butyl-4- { [(5- tert-butyl-2- methoxyphenyl) methyl] amino }-1- [5- methyl-1-
(2- aminomethyl phenyl) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,5- diformazans
Base -1- phenyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4- dihydros -
2H-1,5- benzodioxepins -7- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (2,1- benzoxazoles -3- carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxybenzene
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4- dihydros -
2H-1- chromene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,3- difluoros
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(amyl- 1- of ring
Alkene -1- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(butyl oxide link -
2- yl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(chloro- 3- of 5-
Fluorine pyridine -2- base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(R*) -2-
(the chloro- 3- methyl-1 H- pyrazol-1-yl of 4-) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [5- oxo -1-
(propane -2- base) pyrrolidines -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- cyclopropyl -
5- oxo-pyrrolidine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3- cyano benzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(3aR, 6aS)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -4- ({ [2- first
Oxygroup -4- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (methoxy) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (4- fluorophenyl) -4- [(2- methoxyl group -5- [(1S,
3s)-tricyclic [3.3.1.13,7] decane -1- base] phenyl methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 methoxy quinoline -3- base) methyl] amino } -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- { [(4- methoxyl group [1,1 '-connection
Benzene] -3- base) methyl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyrrolidin-1-yl) pyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -1- (cyclohexane carbo) -3- (2-
Methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -1- (cyclohexane carbo) -3- (2- methoxy
Base propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxyl group -4 '-methyl [1,1 '-biphenyl] -3-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- methoxypyridine -3- base)
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [2.2.1] heptane -2- base) -2- methoxypyridine -3- base] methyl } amino) -
1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxypyridine -3- base) methyl] amino } -
3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxypyridine -3- base] methyl }
Amino) -3- (2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5- (propane -
2- yl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- cyclobutyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3- (2-
Methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclopenta -2- methoxyphenyl) methyl] amino } -3- (2-
Methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- { [(5- cyclohexyl -2- methoxyphenyl) methyl] amino } -3- (2-
Methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -5- (propane -
2- yl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxypyridine -3- base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -3- tert-butyl -1- (cyclohexane carbo) -
5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2- methyl-prop
Oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S*) -2,3- dihydro -1- benzofuran -2- carbonyl] -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- methoxyl group -
3- methylbutyryl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2Rm,
3S*) -3- methyl butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2Sm,
3Rm) -3- methyl butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2Rm) -2-
(3- chlorphenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2Sm) -2-
(3- chlorphenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2Rm) -2,
3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (2- methoxyl group -3- methylbutyryl) -4- ({ [2- methoxyl group -5- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1- [(2R*,
3S*) -3- methyl butyl oxide link -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (sulphur benzene -2- base) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (furans -3- base) -2- methoxyphenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3 ', 4- dimethoxy [1,1 '-biphenyl] -3- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (6- picoline -3- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxyl group -2 '-methyl [1,1 '-biphenyl] -3-
Base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (4- picoline -3- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3 '-cyano -4- methoxyl groups [1, l '-biphenyl] -3- base) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4 '-fluoro- -2 '-methyl of 4- methoxyl group [1,1 '-connection
Benzene] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 ', 4 '-two fluoro- 4- methoxyl group [1,1 '-connection
Benzene] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (pyridin-3-yl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (3,5- dimethyl -1,2-oxazole -4- base) -
2- methoxyphenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2 ', 3 '-two fluoro- 4- methoxyl group [1,1 '-connection
Benzene] -3- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (5- fluorine pyridin-3-yl) -2- methoxybenzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- picoline -3- base) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4 '-cyano -4- methoxyl groups [1,1 '-biphenyl] -3- base) methyl] amino } -
1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (1- cyclobutyl -1H- pyrazoles -4- base) -2- methoxyphenyl] methyl }
Amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (furans -2- base) -2- methoxyphenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (difluoro-methoxy) -2- methoxyphenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,5-dihydrofuran -3- base) -2- methoxyl group
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -5- (2-
Methoxyphenyl) -3- (2- methoxy propane -2- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -3- (2- methoxy propane -2- base) -4-
({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3- methoxyl group -6- phenylpyridine -2- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -2-
Methoxyl group -3,3- dimethylbutanoyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -2- first
Oxygroup -3,3- dimethylbutanoyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,4- dihydro -1H-2- chromene -3- carbonyl) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,4- dihydros -
1H-2- chromene -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- [(2,
6- difluorophenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexane carbo) -3- (1-
Methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -3-
(1- methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (4,
4,4- tri- fluoro- 2- methylbutyryls) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (3- fluorobenzene
Oxygroup) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- methyl ring
Butane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (4- fluorobenzene
Base) cyclopropane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -2- first
Oxygroup propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,2- diformazans
Basic ring propane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (4- fluorobenzene
Oxygroup) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -2- first
Oxygroup propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (2- chlorobenzene
Oxygroup) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclobutane carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3- dihydros -
1- benzothiophene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (cyclopropane
Carbonyl) piperidines -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- methoxyl group -
1,2,3,4- naphthane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (oxane -2- carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -2- benzene
Oxygroup propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (6- fluoro- 3,4-
Dihydro -2H-1- chromene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (amyl- 3- of ring
Alkene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R)-oxygen penta
Ring -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (2,3- bis-
Methylphenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (2- fluorobenzene
Oxygroup) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [2-
(Phenylsulfanyl) propiono] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(2S) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,2- difluoros
Cyclopropane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3- diformazans
Basic ring butane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- ethyl fourth
Acyl group) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (3- chlorobenzene
Oxygroup) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [2-
(pyridin-4-yl) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (pentamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclopropanecarbonyl-
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3- difluoros
Pentamethylene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- fluorine ring fourth
Alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3- difluoros
Cyclobutane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,3- dihydros -
1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- is [anti-
Formula -2- cyclo-propane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (oxane -4- base) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (3- methoxyphenyl) pyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (2- aminomethyl phenyl) pyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (4- fluoro-2-methylbenzene base) -2- methoxyl group pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,4- difluorophenyl) -2- methoxypyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxyl group [3,3 '-two pyridine] -5- base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,3- difluorophenyl) -2- methoxypyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (4- aminomethyl phenyl) pyridine -3-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxyl group -2 '-methyl [3,3 '-two pyridine] -
5- yl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (3,6- dihydro -2H- pyrans -4- base) -2- first
Oxygroup pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,5-dihydrofuran -3- base) -2- methoxyl group
Pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(5- cyclopropyl -2- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- [({ 2- methoxyl group -5- [1- (three
Methyl fluoride) cyclopropyl] phenyl } methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (4- fluorobenzene
Base) -5- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (1- tert-butyl -5- cyano-IH- pyrazoles -4- carbonyl) -4- { [(5- tert-butyl -
2- methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (2,4- bis-
Fluorophenyl) -5- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (4- methoxy
Base phenyl) -5- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- methyl -5-
Phenyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [5- ethyl -1-
(4- fluorophenyl) -3- methyl-1 H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- tert-butyl -
5- (trifluoromethyl)-IH- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S)-3- tert-butyl-4- { [(5- tert-butyl-2- methoxyphenyl) methyl] amino }-1- (5- methyl-1-
Phenyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (ethyl -3 1-,
5- dimethyl -1H- pyrazoles -4- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (methyl -4 2-,
5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (4,
5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (5- methoxyl group -
2,3- dihydro -1H- indenes -1- carbonyls) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -4- first
Oxy-1-methyl-2,3- dihydro-IH- indenes-1- carbonyl]-5- Phenylpyrrolidine-2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (chloro- 1- first of 4-
Base -2,3- dihydro-IH- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (methyl -2 1-,
3- dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (5- chloro- 2,3-
Dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (3-
Phenyl -2,3- dihydro -1- benzofuran -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- hydroxyl -3-
Methylvaleryl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hydroxyl -3 3-,
4- dimethyl-penten acyl group) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -3-Methoxy Pyridine -2- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [4-
(trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1s, 3R,
5S) -3,5- dimethyl cyclohexane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (4,
7,7- trimethyl bicyclics [4.1.0] heptane -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4,4- difluoros
Hexamethylene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [2-
(trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [trans- -4- hydroxyl
Base -4- (propyl- 2- alkene -1- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (trans- -4- second
Base -4- hydroxycyclohexan -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl _ 4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [trans- -4- hydroxyl
Base -4- (propane -2- base) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (trans- -4- hydroxyl
Base -4- propyl cyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (butoxy carbonyl) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
{ [(propyl- 2- alkynes -1- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(amyl oxygen
Base) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- ([(1S, 2R,
5S) -5- methyl -2- (propane -2- base) cyclohexyl] oxygroup } carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- { [(butyl- 3- alkene -1- base) oxygroup] carbonyl } -3- tert-butyl -4- { [(5- tert-butyl -2- methoxy
Base phenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (methoxyl group carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(butyl- 2-
Alkynes -1- base) oxygroup] carbonyl } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (third
Epoxide carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
{ [(propyl- 2- alkene -1- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,2- diformazans
Base propoxyl group) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -2- first
Oxygroup -2- phenyl acetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(1- methoxycyclohexyl) methyl] amino } -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S) -2-
(3,4- difluorophenyl) -2- Methoxyacetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1- (6- first
Base -3,4- dihydro -2H-1- chromene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of 7-) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [2- (4- chlorophenoxy) -3- methylbutyryl] -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [5- (1- anocy clopropyl) -2- methoxyphenyl] methyl } amino) -1-
(cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3- diformazans
Cyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (8- methoxyl group -
3,4- dihydro -2H-1- chromene -3- carbonyls) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [2- (two rings [2.2.1] heptane -2- base) -5- methoxypyridine -4- base] methyl } amino) -
3- tert-butyl -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- cyclohexyl -5- methoxypyridine -4- base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [5-
(2- fluorophenyl) -2- methoxypyridine -3- base] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,4- difluorophenyl) -2- methoxypyridine -
3- yl] methyl } amino) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,6- Dimethoxyphenyl) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [3- methoxyl group -6- (trifluoromethyl) pyridine -2-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [5-
(4- fluoro-2-methylbenzene base) -2- methoxypyridine -3- base] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2-
Methoxyl group -5- (4- aminomethyl phenyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- fluorine hexamethylene -
1- alkene -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (6- chloro- 2,3-
Dihydro -1H- indenes -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [3- methyl -2-
(2- methylphenoxy) bytyry] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (the fluoro- 4- aminomethyl phenyl of 2-) -5- methoxyl group pyrrole
Pyridine -4- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- fluorophenyl) -5- methoxypyridine _ 4-
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- methoxyl group -2- (3- methoxyphenyl) pyridine -
4- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -3- (2- methoxy propane -2-
Base) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- methoxyl group -5- [1- (methoxy) cyclopropyl
Base] phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -2,
3- dihydro -1- benzofuran -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2,2- bis- fluoro- 1- methylcyclopropyl groups) -2- first
Oxygroup pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- { [(2- methoxyl group -5- phenyl pyrazoline
Pyridine -3- base) methyl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- ({ [5- (2- fluorophenyl) -2- first
Oxygroup pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5-
Phenyl -1- [(2R*, 5S*) -5- phenyl butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- [(2-
Aminomethyl phenyl) acetyl group] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (3,3-
Dimethylcyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- [(2-
Aminomethyl phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R*) -2,3- dihydro -1- benzofuran -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1R*, 3aR*, 6aS*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1S*, 3aS*, 6aR*)-hexahydro -1H- ring penta [c] furans -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R) -2- methoxyl group -2- phenyl acetyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (5,5- dimethyl butyl oxide link -2- carbonyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of 7-) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -5- (2- methoxypyridine -3- base) -
4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -3- (2- methoxy propane -
2- yl) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -3,
4- dihydro -2H-1- chromene -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- { (4E) -2- [(2E)-but-2-ene-l- base] hex- 4- enoyl- } -3- tert-butyl -4- { [(5-
Tert-butyl -2- methoxyphenyl) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methylcyclopropyl groups) pyridine -
3- yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S) -3,3- difluorocyclohex alkane-l- carbonyl] -4- ({ [2- methoxyl group -5- (three
Methyl silicane base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (6- oxaspiro
[2.5] octane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (oxa- ring fourth
Alkane -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3R*) -1-
Methyl -2- oxo-piperidine -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,5- diformazan
Base -1H- pyrazoles -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
(7- methyl -2,3- dihydro -1- benzofuran -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(4- methoxyl group [1,1 '-connection
Benzene] -3- base) methyl] amino } -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(1S*, 3S*) -3- methoxycyclohexyl alkane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(1R*, 3R*) -3- methoxycyclohexyl alkane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(4- methoxyl group [1,1 '-connection
Benzene] -3- base) methyl] amino } -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
[(2R)-is disliked (2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1-
Alkane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of (2S*) -7-] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of (2R*) -7-] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { (2R*) -2-
[(2S*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { (2S*) -2-
[(2R*)-oxane -2- base] propiono } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(1S*, 3R*) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (oxane -
2- yl) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [cis- -4- hydroxyl
Base -4- (trifluoromethyl) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [trans- -4- hydroxyl
Base -4- (trifluoromethyl) hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- fluorobenzene
Base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2-
Methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [4- hydroxyl -4- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- (4- phenoxybenzoyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- { 4- [(oxane -4- base) oxygroup] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- { 4- [(pyridine -2- base) oxygroup] benzoyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [4- (trifluoromethoxy) benzoyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4,4- difluoros
Hexamethylene -1- carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- (3,5- dimethyl cyclohexane -1- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R*) -2,
3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2S*) -2,
3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(1R*, 2R*, 3S*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl
Base] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1-
[(2R*) -2,3- dihydro-Isosorbide-5-Nitrae-benzo dioxin -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (2,3-
Dihydro-Isosorbide-5-Nitrae-benzo dioxin -6- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (6-
Fluoro- 3,4- dihydro -2H-1- chromene -2- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- tert-butyl -4- methoxy pyrimidine -5- base) methyl] amino } -1-
[(1R*) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- [(1R, 3R) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3R*) -3,
4- dihydro -1H-2- chromene -3- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3S*) -3,
4- dihydro -1H-2- chromene -3- carbonyl] -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of (2S) -6-] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -5- [2- (dimethylamino) pyridine -
3- yl] -4- { [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] amino } -1- [(1R, 2R) -2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
L- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) -5- [2- (dimethylamino) pyridine -3-
Base] -4- { [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (difluoro first
Oxygroup) pyridin-3-yl] -1- [(2R*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (difluoro first
Oxygroup) pyridin-3-yl] -1- [(2S*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- (oxane -2- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (3,3-
Difluorocyclohex alkane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (1- first
Tetramethylcyclobutyl) phenyl] methyl } amino) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- cyclobutyl -3- methoxyl group pyridazine -4- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [3- (3- chlorobenzene
Base) oxetanes -3- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (two ring of 3- fluorine
[1.1.1] pentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [1- (2,2- bis- fluoro- 2H-1, dioxy between 3- benzo
Heterocyclic pentene -5- base) cyclopropyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [2- (4- chlorphenyl) -2- methyl-propyl] amino } -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -5- [2-
(dimethylamino) pyridin-3-yl] -3- (2- methoxy propane -2- base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -
2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -4- (fluoroform
Base) pyridine -2- base] amino } -1- [2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) -5- [2- (dimethylamino) pyridine -3-
Base] -4- { [6- methyl _ 4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -4- (fluoroform
Base) pyridine -2- base] amino } -1- [(2S*)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(1R*, 2R*, 3R*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(1S*, 2S*, 3S*, 4R*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (difluoro first
Oxygroup) phenyl] -1- [(1R*, 2R*, 3R*, 4S*) -3- (trifluoromethyl) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrole
Cough up alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluorocyclohex alkane -1- carbonyl) -4- ({ [2- methoxyl group -4- (fluoroform
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- [(1S) -3,3- difluorocyclohex alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) benzene
Base] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R, 3S) -
3- hydroxycyclohexan -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- [(1S, 3S) -3- methoxycyclohexyl alkane -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (two rings [3.1.0] hexane -6- carbonyl) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxyl group
Pyridin-3-yl) methyl] amino } -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- fluorine
Phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- [(1S*, 2R*, 4R*) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethoxy) phenyl] methyl } amino) -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxy
Base -5- (trifluoromethoxy) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- (2- fluorophenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R, 3S) -
3- hydroxy-3-methyl hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- [({ 2- methoxy
Base -5- [(trifluoromethyl) sulfanyl] phenyl } methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- (hexamethylene
Alkyl carbonyl) -5- [2- (difluoro-methoxy) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 2- methoxyl group -5- [(trifluoromethyl) sulfanyl] phenyl } methyl) amino] -
5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- fluorine
Phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- [(1R,
3R) -3- fluorine hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R, 3R) -
3- hydroxy-3-methyl hexamethylene -1- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ 2- methoxyl group -5- [(1S, 3s)-tricyclic [3.3.1.13,7] decane -1- base]
Phenyl } methyl) amino] -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (five fluoro- λ6Sulfanyl) phenyl] methyl } amino) -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R, 2S,
4S) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R, 3S) -3- hydroxycyclohexan -1- carbonyl] -4- ({ [2- methoxyl group _ 4-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- [(2S) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methoxyl group
Pyridin-3-yl) -1- [(1R, 3R) -3- (trifluoromethoxy) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) benzene
Base] methyl } amino) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethoxy)
Phenyl] methyl } amino) -1- [(2R) -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R, 2S,
4S) -7- oxabicyclo [2.2.1] heptane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- fluorophenyl) -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] first
Base } amino) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(4- methoxyl group [1,1 '-connection
Benzene] -3- base) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- methoxynaphthalene -2- base) methyl] amino } -5- phenyl -1- { [(propane -
2- yl) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (trifluoro
Methoxyl group) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4R, 5S) -3- tert-butyl -4- { [(3- methoxynaphthalene -2- base) methyl] amino } -5- phenyl -1- { [(propane -
2- yl) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4R, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4R, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- (3- first
Base bytyry) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [1- (three
Methyl fluoride) cyclopropyl] phenyl } methyl) amino] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethoxy) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- { [(third
Alkane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(3- methoxynaphthalene -2- base)
Methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(6- methoxyl group -2,3- bis-
Hydrogen -1H- indenes -5- base) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- methyl fourth
Acyl group) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(3- methoxyl group -5,6,7,8-
Naphthane -2- base) methyl] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- fluorine
Phenyl) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- { [(propane -2- base)
Oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (dimethylamino
Base) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1S) -6- first
Oxy-1-methyl-2,3- dihydro-1H- indenes-1- carbonyl]-5- (2- methoxypyridine-3- base) pyrrolidines-2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(1R) -6- first
Oxy-1-methyl-2,3- dihydro-1H- indenes-1- carbonyl]-5- (2- methoxypyridine-3- base) pyrrolidines-2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S, 3S) -3- methoxycyclohexyl alkane -1- carbonyl] -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1R) -3,3- difluorocyclohex alkane -1- carbonyl] -5- (2- methoxypyridine -3-
Base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxypyridine -3- base) -4- ({ [2- methoxy
Base -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- aminomethyl phenyl) -4- { [6- methyl -4- (fluoroform
Base) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- (2- aminomethyl phenyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (pyrroles
Alkane -1- base) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -5-
(2- aminomethyl phenyl) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl .4- { [(2 methoxy quinoline -3- base) methyl] amino } -5- (2- aminomethyl phenyl) -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5-
(2- aminomethyl phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- (2- first
Base phenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- (2- methylbenzene
Base) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- [({ 1- [(benzyloxy) carbonyl] piperidines -3- base } methyl) amino] -3- tert-butyl -5- phenyl -
1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- ({ [3- (trifluoromethyl)
Cyclohexyl] methyl } amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- first
Base phenyl) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl pyridine -3- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrazole, pyrrole alkane -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- (2- cyclopropyl pyridine -3- base) -4- ({ [2- methoxyl group -4- (trifluoromethyl) benzene
Base] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- (2- ring
PropyIpyridine -3- base) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- difluoro pentamethylene -1- carbonyl) -4- ({ [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxy-propio] -4- ({ [2- methoxyl group -5- (trifluoromethyl)
Pyridin-3-yl] methyl } amino) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
(oxane -4- carbonyl) -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -5- [2- (azetidine -1- base) pyridin-3-yl] -3- tert-butyl -4- ({ [2- methoxyl group -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -1-
[(2S)-butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxypyridine -3- base of 5-) methyl] amino } -3- tert-butyl -1- [(2S)-oxygen
Penta ring -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(difluoromethyl) phenyl] -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2 methoxy quinoline -3- base) methyl] amino } -1- (oxane -4- carbonyl) -
5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(2 methoxy quinoline -3-
Base) methyl] amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [(2 methoxy quinoline -3-
Base) methyl] amino } -1- (oxane -4- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- chlorphenyl) methyl] amino } -1- (Cyclopentylacetyl) -
5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Cyclopentylacetyl) -4- { [(2- aminomethyl phenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Cyclopentylacetyl) -4- { [(2,4- dichlorophenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [4- (trifluoromethyl) pyridine -
2- yl] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- { [5- (trifluoromethyl) pyridine -
2- yl] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(4- chloropyridine -2- base) amino] -1- (cyclohexane carbo) -5- benzene
Base pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoro-methoxy) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [(6- methoxypyridine -2- base) amino] -
5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(3- chlorine-2-hydroxyl phenyl) methyl] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 6- [(oxane -4- base) oxygroup] pyrrole
Pyridine -2- base } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,5- Dimethoxyphenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,3- Dimethoxyphenyl) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3- methoxyphenyl) methyl] ammonia
Base } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 4- Dimethoxyphenyl of 3-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4-methoxypyridine -3- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- methoxyl group -4- (trifluoromethyl) pyrrole
Pyridine -2- base] (methyl) amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [(2,2- bis- fluoro- 2H-1, two between 3- benzo
Oxole -5- base) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxypyridine -2- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 4- Dimethoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3-Methoxy Pyridine -2- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(4- methoxy pyrimidine -2- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [6- oxo -4- (trifluoromethyl) -1,6-
Dihydropyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [1- (2- methoxy ethyl) -1H- miaow
Azoles -2- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(6- methoxypyridine -3- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(chloro- 2, the 3- Dimethoxyphenyl of 5-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (morpholine -4- base) pyridin-3-yl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,4- dimethoxypyridin -5- base)
Methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [1- oxo -4- (trifluoromethyl) -1 λ5-
Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R)-3- tert-butyl-1- (cyclohexane carbo)-4- { [6- methyl-1-oxo-4- (fluoroform
Base) -1 λ5Pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- cyclopropyl -5- phenyl -4- { [4- (trifluoromethyl) pyridine -
2- yl] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -1- [two (propane -2- bases)
Carbamoyl] -3- methyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -4- (trifluoromethyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (dimethylamino) -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- [two (propane -2- base) ammonia
Base formoxyl] -3- methyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- { [4- (three
Methyl fluoride) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- [two (propane -2- base) ammonia
Base formoxyl] -3- methyl -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2- methoxy
Base -4- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -
4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [(4- cyanopyridine -2- base) amino] -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- { [6- (three
Methyl fluoride) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,2- bis- fluoro- 2H-1, between 3- benzo
Dioxol-4 -yl) methyl] amino }-5- (2- methoxyphenyl) pyrrolidines-2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -
4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R) -3- cyclopropyl -1- [two (propane -2- base) carbamoyls] -4- { [6- methyl -4- (trifluoro
Methyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -3- cyclopropyl -1- [two (third
Alkane -2- base) carbamoyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (2- methoxyl group ethylsulfonyl) -4- { [6-
Methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (2- methylpropane -2- sulfonyl) -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (1- methyl cyclopropane -1- sulfonyl) -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (cyclopropanesulfonyl) -4- { [6- methyl -
4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (ethylsulfonyl) -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (DimethylsuIfamoyl) -4- { [6- first
Base -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- [ethyl (methyl) sulfamoyl] -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo)-N- (mesyl) -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formamide；
Racemic-(4R, 6R, 7R) -5- (cyclohexane carbo) -7- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -6- benzene
Base -5- azaspiro [2.4] heptane -4- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -5- (6- first
Oxygroup pyridine -2- base) -1- [(1R, 5S, 6S) -3- oxabicyclo [3.1.0] hexane -6- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- ({ [2- (difluoro-methoxy) phenyl] methyl } amino) -1- [two (third
Alkane -2- base) carbamoyl] -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) benzene
Base] methyl } amino) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- { [6- methyl -4- (fluoroform
Base) pyridine -2- base] amino } -1- (3- oxabicyclo [3.1.0] hexane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- { [6- methyl -4- (fluoroform
Base) pyridine -2- base] amino } -1- (oxane -2- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- methoxy ethoxy) -5-
(trifluoromethyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [1- (2- methoxy ethyl) -2- oxygen
Generation -5- (trifluoromethyl) -1,2- dihydropyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- hydroxyl-oxethyl) -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (6- methoxypyridine -2- base) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -1- (oxane -3- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -5- (6- methoxypyridine -2- base) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -1- [(3R*) -3- methyl oxane -3- carbonyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -1- (3- oxabicyclo [3.1.0] hexane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [the chloro- 5- of 2- (2- methoxy ethoxy) pyridin-4-yl] methyl }
Amino) -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 5- pyridone -4- base of 2-) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- ({ [2- amino -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) tertiary fourth of -3-
Base -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4- (trifluoro
Methyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -4- { [6- (difluoro-methoxy) pyridine -2- base] amino } -5- (6- methoxy
Yl pyridines -2- base) -1- (3- methyl oxane -3- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -1- (3- methyl oxane -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2R) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4- (trifluoro
Methyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- hydroxyl -5- (mesyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- methoxy ethoxy) -5-
(trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyrrole
Pyridine -3- base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5S) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (pyridine -2- base) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2- cyano-phenyl) methyl] amino } -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- [({ 2- [3- (mesyl) propoxyl group] -
5- (trifluoromethyl) phenyl } methyl) amino] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (3- fluorine propoxyl group) -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- [({ 2- [2- (trifluoro methoxy
Base) ethyoxyl] -5- (trifluoromethyl) phenyl } methyl) amino] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (2- hydroxyl-oxethyl) -5- (three
Methyl fluoride) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R*) -2- methoxy
Base -2- phenyl acetyl] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2R) -2- methoxy
Base -2- phenyl acetyl] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- [(2S) -2- methoxy
Base -2- phenyl acetyl] -4- { [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(2,4- Dimethoxyphenyl) methyl] amino } -5- phenyl -1-
{ [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(3- methoxyl group [1,1 '-biphenyl] -4- base) methyl] amino } -5-
Phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -4-
(trifluoromethyl) pyridine -2- base] amino } -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- [2- (dimethylamino) pyridin-3-yl] pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- methoxyphenyl) -4- ({ [2- methoxyl group -4-
(trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -1- [(ring fourth
Base oxygroup) carbonyl] -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -1- (cyclohexane carbo) -5- (6- methoxypyridine -2- base) -4- { [6-
Methyl -4- (trifluoromethyl) pyridine -2- base] amino } pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -5- [2- (dimethylamino) phenyl] -1- [(2R) -2- methoxyl group -2- phenylacetyl
Base] -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 5-) methyl] amino } -5- [2- (dimethylamino
Base) phenyl] -1- [(2R) -2- methoxyl group -2- phenyl acetyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- [(2R) -3,3,3- tri- fluoro- 2- methoxyl group -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- ({ [2- methoxyl group -4- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- [(2R) -3,3,3- tri- fluoro- 2- methoxyl group -2- phenylpropionyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(2S) -2- methoxyl group -2- phenyl acetyl] -4- { [6- methyl -4- (trifluoro
Methyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (4,4- difluorocyclohex alkane -1- carbonyl) -4- { [6- methyl -4- (three
Methyl fluoride) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -
5- phenyl -1- (spiral shell [2.5] octane -6- carbonyl) pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- methoxyl group -2- (trifluoromethyl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- fluoro- 2- (mesyl) phenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the bromo- 2- cyano-phenyl of 5-) methyl] amino } -3- tert-butyl -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- [(1R, 2S, 4S)-two ring [2.2.1] heptane -2- carbonyl] -3- tert-butyl -4-
{ [6- methyl -4- (trifluoromethyl) pyridine -2- base] amino } -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- [(the chloro- 3-Methoxy Pyridine -2- base of 5-) amino] -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -4- [[2- methoxyl group -4- (trifluoromethyl) phenyl] methylamino] -5-
Phenyl -1- [(2R*) -2- phenylpropionyl] pyrrolidines -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- (Isosorbide-5-Nitrae-dioxanes -2- carbonyl) -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -3- tert-butyl -1- [(cyclobutyl oxygroup) carbonyl] -4- ({ [2- methoxyl group -4- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (cyclohexane carbo) -3-
(2- methoxy propane -2- base) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2R, 3R, 4R, 5R) -1- (cyclohexane carbo) -3- (2- methoxy propane -2- base) -4- ({ [2- methoxyl group -
5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -1- [(2R) -
Oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(the bromo- 2- methoxyphenyl of 5-) methyl] amino } -3- tert-butyl -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(3- methoxyl group -5,5,8,8- tetramethyls -5,6,7,
8- naphthane -2- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- dihydro -2H-1- chromene -6- base) first
Base] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(4- cyano -2- fluorophenyl) methyl] amino } -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,3- dihydro -1- benzofuran -5- base) methyl]
Amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- fluoro- 2- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [({ the chloro- 2- of 5- [(propane -2- base) oxygroup] phenyl } methyl) amino] -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- cyano -4- fluorophenyl) methyl] amino } -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- chloro-4-methoxy phenyl) methyl] amino } -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(2- cyano -4- fluorophenyl) methyl] amino } -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [3- fluoro- 4- (trifluoromethoxy) phenyl] methyl }
Amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- dihydro -2H-1,5- benzo dioxa cycloheptyls
Alkene -7- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- dichlorophenyl) methyl] amino } -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- bromo- 2- (difluoro-methoxy) phenyl] methyl } amino) -3- tert-butyl -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2,2- bis- fluoro- 2H-1, dioxane between 3- benzo
Amylene -5- base) methyl] amino } -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,5- Dimethoxyphenyl) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(3,4- 3,5-dimethylphenyl) methyl] amino } -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [(1- benzofuran -5- base) methyl] amino } -3- tert-butyl -1- (cyclohexane carbo) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- fluoro- 4- (trifluoromethyl) phenyl] methyl } ammonia
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [1- (mesyl) cyclopropane -1- carbonyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- phenyl -4- ({ [4- (trifluoromethyl) phenyl] methyl }
Amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- (difluoromethyl) phenyl] methyl } amino) -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(7- chloro- 2H-1,3- benzodioxole -5- base) methyl] ammonia
Base } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [4- (difluoro-methoxy) -3,5- 3,5-dimethylphenyl]
Methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- chloro- 2H-1,3- benzodioxole -5- base) methyl] ammonia
Base } -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
Racemic-(2S, 3S, 4S, 5R) -3- tert-butyl -4- { [(the chloro- 2- methoxyphenyl of 4-) methyl] amino } -1- (hexamethylene
Carbonyl) -5- (3-Methoxy Pyridine -2- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(4- carbamoyl -6- chloropyridine -2- base) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 3- cyano -5- fluorine pyridine -2- base of 6-) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 4- cyanopyridine -2- base of 6-) amino] -1- (cyclohexane carbo) -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [the chloro- 4- of 6- (2- hydroxy propane -2- base) pyridine -2- base] amino } -1- (ring
Hexane carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(3- cyano -4,6- lutidines -2- base) amino] -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- [(the chloro- 3- ethyl quinolinium -2- base of 7-) amino] -1- (cyclohexane carbo) -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- [(6- anilino--nicotinonitrile -2- base) amino] -3- tert-butyl -1- (cyclohexane carbo) -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(7- methoxyl group -4- methylquinoline -2- base) amino] -
5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(4- ethoxyquinoline -2- base) amino] -5- phenyl
Pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ 5- [(2- oxo pyridine -1 (2H)-yl) methyl] pyrrole
Pyridine -2- base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(7- methoxyl group -3- methylisoquinolinium -1- base) ammonia
Base] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (t-Butylcarbamoyl) pyridine -2- base] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(isoquinolin -3- base) amino] -5- Phenylpyrrolidine -
2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(1,3- dimethyl -2,4- dioxo -1,2,3,4-
Tetrahydropyridine simultaneously [4,3-d] pyrimidine -5- base) amino] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (2- dicyanopropane -2- base) pyridine -2- base] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (1- anocy clopropyl) pyridine -2- base] amino } -1- (hexamethylene carbonyl
Base) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- { [3- (benzyloxy) pyridine -2- base] amino } -3- tert-butyl -1- (cyclohexane carbo) -5- benzene
Base pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [5- (t-Butylcarbamoyl) pyridin-3-yl] amino } -1- (hexamethylene
Carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- [(isoquinolin -4- base) amino] -5- Phenylpyrrolidine -
2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -4- (trifluoromethyl) phenyl] methyl } amino) -5- phenyl -
1- (pyridine -3- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5R) -3- tert-butyl -5- (3- chloropyridine -2- base) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5-
(trifluoromethyl) phenyl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -1-
[(2S)-oxane -2- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(4- chlorobenzene
Base) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (cyclohexyl second
Acyl group) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (butane -2- base) -2- methoxyphenyl] methyl } amino) -3- tert-butyl -1- (hexamethylene
Alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (cyclohexyl methyl) -2- methoxyphenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (2- ethyl-butyl) -2- methoxyphenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- phenylethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(3,4- difluoros
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2,4- difluoros
Phenyl) acetyl group] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (4- methyl ring
Hexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3- methyl ring
Hexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1,5- diformazan
Base -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (1- methyl -
1H- indoles -3- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (the fluoro- 2H of 6-,
4H-1,3- benzo dioxin -8- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [2-
(propane -2- base) oxane -4- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- { [(2- oxyquinoline -3- base) methyl] amino } -5-
Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (morpholine -4- base) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(S*) -2-
(the chloro- 3- methyl-1 H- pyrazol-1-yl of 4-) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2-
Methoxyl group -5- (tricyclic [3.3.1.13,7] decane -1- base) phenyl] methyl amino) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (4- methylpiperazine-1-yl) benzene
Base] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- [(1S) -3,3- difluorocyclohex alkane -1- carbonyl] -4- ({ [2- methoxyl group -5- (three
Methyl fluoride) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (1- methyl-1 H- pyrazoles -4-
Base) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [5- (1- cyclopropyl -1H- pyrazoles -4- base) -2- first
Phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (cyclohexane carbo) -5- (2- fluorophenyl) -4- [(2- methoxyl group -5- [(1S,
3S)-tricyclic [3.3.1.13,7] decane -1- base] phenyl methyl) amino] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } ammonia
Base) -3- (1- methylcyclopropyl groups) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [2- (3,5- bis-
Methylphenoxy) propiono] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- (1,
2,3,4- naphthane -2- carbonyls) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1-
[(1R, 5S)-tricyclic [3.2.1.02,4] octane -3- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- phenyl -1- [2-
(sulphur benzene -2- base) cyclopropane -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [1- (3- methyl
Phenyl) -5- (propane -2- base) -1H- pyrazoles -4- carbonyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2- methyl ring
Hexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,5- dimethyl cyclohexane -1- carbonyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,3- dimethylcyclopentane -1- carbonyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) phenyl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] methyl } amino) -1- (3- first
Cyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2R, 3R, 4R, 5S) -3- tert-butyl -1- (cyclohexane carbo) -4- ({ [2- methoxyl group -5- (trifluoromethyl) phenyl] first
Base } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] methyl } amino) -5-
Phenyl -1- { (2R, 3R) -3- [(1H- pyrazol-1-yl) methyl] butyl oxide link -2- carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -1- (3,5- dimethyl cyclohexane -1- carbonyl) -4- ({ [2- methoxyl group -5- (trifluoro
Methyl) pyridin-3-yl] methyl } amino) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- (cyclohexane carbo) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (3,3- diformazans
Butylcyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (2,2- diformazans
Cyclopentane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- (2- hexahydrotoluene -1- carbonyl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (tert-butyl) -4- (((5- cyclobutyl -2- methoxypyridine -3- base) methyl) amino) -1- (3,
5- dimethyleyelohexane alkyl carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -1- (2- first
Butylcyclohexane -1- carbonyl) -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- phenyl -
1- [3- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -5- [2- (dimethyl
Amino) pyridin-3-yl] -1- [(2R*) fluoro- 3, the 4- dihydro -2H-1- chromene -2- carbonyl of -6-] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -1- (cis- -4- hydroxyl -4- propyl
Hexamethylene -1- carbonyl) _ 4- { [2- methoxyl group -5- (trifluoromethyl) pyridin-3-yl] amino } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] amino } -1- [(1S, 2S) -2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [2- methoxyl group -5- (fluoroform
Base) pyridin-3-yl] amino } -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- phenyl -
1- [2- (trifluoromethyl) hexamethylene -1- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(2R) -2- first
Oxygroup -2- phenyl acetyl] -2- methyl -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- { [6- methyl -4- (fluoroform
Base) pyridine -2- base] amino } -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [two (propane -
2- yl) carbamoyl] -5- Phenylpyrrolidine -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -5- [2- (difluoro-methoxy) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- tert-butyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -4- ({ [5- (two rings [1.1.1] pentane -1- base) -2- methoxyphenyl] methyl } amino) -3- uncle
Butyl -1- { [(propane -2- base) oxygroup] carbonyl } -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane-l- base) -4- ({ [2- methoxyl group -5- (trifluoromethyl) pyridine -3-
Base] methyl } amino) -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- (two rings [1.1.1] pentane -1- base) -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] ammonia
Base } -5- (2- fluorophenyl) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [(2- methoxyl group -5- [(3S,
5S)-tricyclic [3.3.1.13,7] decane -1- base] phenyl methyl) amino] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -
2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl] amino } -5- [2-
(dimethylamino) pyridin-3-yl] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- [({ 2- methoxyl group -5- [(trifluoro
Methyl) sulfanyl] phenyl } methyl) amino] -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(6- methoxyl group -2,3- dihydro -1H- indenes -5- base) methyl] amino } -5- benzene
Base -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(3- methoxyl group -5,5,8,8- tetramethyls -5,6,7,8- naphthane -2- bases)
Methyl] amino } -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
Racemic-(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- (ring
Hexane carbonyl) -5- (1- methyl -2- oxo -1,2- dihydropyridine -3- base) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- { [(propane -2-
Base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- { [(5- tert-butyl -2- methoxyphenyl) methyl] amino } -1- [(7S) -2,2-
Two fluoro- 7- methyl -6,7- dihydro -2H- furans simultaneously [2,3-f] [1,3] benzodioxole -7- carbonyl] -5- (2- first
Oxygroup pyridin-3-yl) pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (trifluoromethoxy) phenyl] methyl } amino) -1-
{ [(propane -2- base) oxygroup] carbonyl } -5- { 2- [(propane -2- base) oxygroup] pyridin-3-yl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- [2- (dimethylamino) pyridin-3-yl] -4- ({ [2- methoxyl group -5- (2- first
Base butane -2- base) phenyl] methyl } amino) -1- { [(propane -2- base) oxygroup] carbonyl } pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -5-
(2- methoxypyridine -3- base) -1- [(2S)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- methoxyl group -5- (1- methyl-cyclobutyl) phenyl] methyl } amino) -5-
(2- methoxypyridine -3- base) -1- [(2R)-oxane -2- carbonyl] pyrrolidines -2- formic acid；
(2S, 3S, 4S, 5S) -3- tert-butyl -5- phenyl -1- { [(propane -2- base) oxygroup] carbonyl } -4- ({ [1- (propane -2-
Base) piperidin-4-yl] methyl } amino) pyrrolidines -2- formic acid；
(2R, 3R, 4R, 5R) -3- tert-butyl -5- (2- chlorphenyl) -4- { [(5- cyclobutyl -2- methoxypyridine -3- base) methyl]
Amino } -1- [(2S)-butyl oxide link -2- carbonyl] pyrrolidines -2- formic acid；And
(2S, 3S, 4S, 5S) -3- tert-butyl -4- ({ [2- hydroxyl -5- (methoxycarbonyl) phenyl] methyl } amino) -1- [(2S) -
Butyl oxide link -2- carbonyl] -5- [2- (propane -2- base) phenyl] pyrrolidines -2- formic acid.
10. a kind of pharmaceutical composition, the pharmaceutical composition include therapeutically effective amount, combined with pharmaceutically acceptable carrier
Compound or its pharmaceutically acceptable salt as described in claim 1 with formula (I).
11. compound as described in claim 1 or its pharmaceutically acceptable salt or medicine group as claimed in claim 10
Object is closed, for using in medicine.
12. compound as described in claim 1 or its pharmaceutically acceptable salt or medicine group as claimed in claim 10
Object is closed, for using in the treatment of cystic fibrosis.
13. a kind of method for treating the cystic fibrosis of subject, this method includes giving to control to subject in need
Treat compound or its pharmaceutically acceptable salt a effective amount of, according to claim 1, with formula (I).
14. a kind of pharmaceutical composition, which includes compound as described in claim 1 or its is pharmaceutically acceptable
Salt, a kind of synergist and one or more other corrigents.
15. a kind of method for treating the cystic fibrosis of subject, this method include given to subject in need as
Compound described in claim 1 or its pharmaceutically acceptable salt, a kind of synergist and one or more other corrections
Agent.
16. a kind of pharmaceutical composition, which includes compound as described in claim 1 or its is pharmaceutically acceptable
Salt and one or more other therapeutic agents.
17. pharmaceutical composition as claimed in claim 16, wherein the other therapeutic agent is selected from the group, the group is by with the following group
At: CFTR regulator and CFTR reinforcing agent.
18. pharmaceutical composition as claimed in claim 16, wherein the other therapeutic agent is CFTR regulator.
19. a kind of method for treating the cystic fibrosis of subject, this method includes giving as described in claim 1ization
Close object or its pharmaceutically acceptable salt and one or more other therapeutic agents.
20. method as claimed in claim 19, wherein the other therapeutic agent is selected from the group, which is made up of:
CFTR regulator and CFTR reinforcing agent.
21. method as claimed in claim 19, wherein the other therapeutic agent is CFTR regulator.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662405598P | 2016-10-07 | 2016-10-07 | |
| US62/405598 | 2016-10-07 | ||
| PCT/IB2017/056196 WO2018065962A1 (en) | 2016-10-07 | 2017-10-06 | Substituted pyrrolidines and their use in the treatment of cystic fiibrosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110036009A true CN110036009A (en) | 2019-07-19 |
Family
ID=60268420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780075081.3A Pending CN110036009A (en) | 2016-10-07 | 2017-10-06 | Substituted pyrrolidines and their use in the treatment of cystic fibrosis |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US9981910B2 (en) |
| EP (1) | EP3523293B1 (en) |
| JP (1) | JP2019537564A (en) |
| CN (1) | CN110036009A (en) |
| AU (1) | AU2017339249A1 (en) |
| BR (1) | BR112019007039A2 (en) |
| CA (1) | CA3039659A1 (en) |
| MX (1) | MX2019004018A (en) |
| WO (1) | WO2018065962A1 (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3798214B1 (en) | 2014-10-06 | 2022-09-14 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| HUE056716T2 (en) | 2016-09-30 | 2022-03-28 | Vertex Pharma | Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
| DK3551622T3 (en) | 2016-12-09 | 2020-11-23 | Vertex Pharma | MODULATOR OF TRANSMEMBRANE CONDUCTANCE REGULATOR OF CYSTIC FIBROSE, PHARMACEUTICAL COMPOSITIONS, TREATMENT PROCEDURES AND METHOD OF MANUFACTURE OF THE MODULATOR |
| TW201831471A (en) | 2017-02-24 | 2018-09-01 | 盧森堡商艾伯維公司 | Modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use |
| CA3066084A1 (en) | 2017-06-08 | 2018-12-13 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| CA3069226A1 (en) | 2017-07-17 | 2019-01-24 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
| AU2018309043B2 (en) | 2017-08-02 | 2022-03-31 | Vertex Pharmaceuticals Incorporated | Processes for preparing pyrrolidine compounds |
| US10988454B2 (en) | 2017-09-14 | 2021-04-27 | Abbvie Overseas S.À.R.L. | Modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use |
| TWI719349B (en) | 2017-10-19 | 2021-02-21 | 美商維泰克斯製藥公司 | Crystalline forms and compositions of cftr modulators |
| AU2018380426B2 (en) | 2017-12-08 | 2023-05-18 | Vertex Pharmaceuticals Incorporated | Processes for making modulators of cystic fibrosis transmembrane conductance regulator |
| TWI810243B (en) | 2018-02-05 | 2023-08-01 | 美商維泰克斯製藥公司 | Pharmaceutical compositions for treating cystic fibrosis |
| JP7214743B2 (en) | 2018-02-15 | 2023-01-30 | バーテックス ファーマシューティカルズ インコーポレイテッド | Macrocycles as modulators of cystic fibrosis transmembrane conductance regulators, pharmaceutical compositions thereof, their use in the treatment of cystic fibrosis, and methods for their preparation |
| WO2019200246A1 (en) | 2018-04-13 | 2019-10-17 | Alexander Russell Abela | Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
| JP7576552B2 (en) | 2019-01-18 | 2024-10-31 | バイオジェン・エムエイ・インコーポレイテッド | Imidazo[1,2-a]pyridinyl derivatives and their use in the treatment of diseases - Patents.com |
| US11345691B2 (en) | 2019-06-03 | 2022-05-31 | AbbVie Global Enterprises Ltd. | Prodrug modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use |
| TW202115014A (en) | 2019-07-12 | 2021-04-16 | 美商奧佛麥德公司 | Compound for treating cystic fibrosis |
| EP4013760A1 (en) | 2019-08-14 | 2022-06-22 | Vertex Pharmaceuticals Incorporated | Crystalline forms of cftr modulators |
| TW202120517A (en) | 2019-08-14 | 2021-06-01 | 美商維泰克斯製藥公司 | Process of making cftr modulators |
| TW202115092A (en) | 2019-08-14 | 2021-04-16 | 美商維泰克斯製藥公司 | Modulators of cystic fibrosis transmembrane conductance regulator |
| US20220211692A1 (en) | 2021-01-06 | 2022-07-07 | AbbVie Global Enterprises Ltd. | Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein and Methods of Use |
| WO2022150173A1 (en) | 2021-01-06 | 2022-07-14 | AbbVie Global Enterprises Ltd. | Modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use |
| WO2024084363A1 (en) | 2022-10-18 | 2024-04-25 | Pfizer Inc. | Use of patatin-like phospholipase domain-containing protein 3 compounds |
| WO2024084360A1 (en) | 2022-10-18 | 2024-04-25 | Pfizer Inc. | Patatin-like phospholipase domain-containing protein 3 (pnpla3) modifiers |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008147952A1 (en) * | 2007-05-25 | 2008-12-04 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| WO2009003009A1 (en) * | 2007-06-26 | 2008-12-31 | Enanta Pharmaceuticals, Inc. | Substituted pyrrolidine as anti-infectives |
| US20100168094A1 (en) * | 2008-12-30 | 2010-07-01 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| US20100184739A1 (en) * | 2004-06-24 | 2010-07-22 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette Transporters |
| US20110230483A1 (en) * | 2010-03-19 | 2011-09-22 | Novartis Ag | Pyridine and Pyrazine derivative for the Treatment of CF |
| CN105531268A (en) * | 2013-05-07 | 2016-04-27 | 加拉佩格斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis |
| WO2016069757A1 (en) * | 2014-10-31 | 2016-05-06 | Abbvie Inc. | Substituted chromanes and method of use |
| CN105658655A (en) * | 2013-08-08 | 2016-06-08 | 加拉佩格斯股份有限公司 | Thieno[2,3-C]pyrans as CFTR modulators |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2569402A1 (en) | 2004-06-04 | 2005-12-22 | The Regents Of The University Of California | Compounds having activity in increasing ion transport by mutant-cftr and uses thereof |
| NZ587547A (en) | 2004-06-24 | 2012-09-28 | Vertex Pharma | Modulators of ATP-Binding Cassette Transporters |
| AU2008334629B2 (en) | 2007-12-10 | 2012-04-12 | Novartis Ag | Organic compounds |
| CN101925603B (en) | 2007-12-13 | 2013-12-04 | 沃泰克斯药物股份有限公司 | Modulators of cystic fibrosis transmembrane conductance regulator |
| US8436014B2 (en) | 2008-10-23 | 2013-05-07 | Vertex Pharmaceutical Incorporated | Solid forms of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluorormethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihyroquinoline-3-carboxamide |
| AU2011311920B2 (en) | 2010-10-08 | 2015-06-11 | Laurel Therapeutics Ltd | Novel substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors |
| WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
| JP6165733B2 (en) | 2011-09-16 | 2017-07-19 | ノバルティス アーゲー | N-substituted heterocyclylcarboxamides |
| WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| CN103946221B (en) | 2011-09-16 | 2016-08-03 | 诺华股份有限公司 | For treating the heterocyclic compound of cystic fibrosis |
| PL2760463T3 (en) | 2011-09-20 | 2019-05-31 | Univ North Carolina Chapel Hill | Regulation of sodium channels by plunc proteins |
| WO2015138909A1 (en) | 2014-03-13 | 2015-09-17 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing cftr activity |
| EP3116870A1 (en) | 2014-03-13 | 2017-01-18 | Proteostasis Therapeutics, Inc. | Compounds, compositions, and methods for increasing cftr activity |
| KR102520483B1 (en) | 2014-10-02 | 2023-04-12 | 다우 글로벌 테크놀로지스 엘엘씨 | High frequency weldable ethylene-based polymer compositions with good flame retardancy |
| AU2015339196A1 (en) | 2014-10-31 | 2017-05-11 | Abbvie S.A.R.L. | Substituted tetrahydropyrans and method of use |
| CN107922338A (en) | 2015-06-02 | 2018-04-17 | 艾伯维公司 | The pyridine and application method being substituted |
| US9840513B2 (en) | 2015-07-16 | 2017-12-12 | Abbvie S.Á.R.L. | Substituted tricyclics and method of use |
| MX2018004364A (en) | 2015-10-09 | 2018-08-16 | Abbvie Sarl | Substituted pyrazolo[3,4-b]pyridin-6-carboxylic acids and their use. |
| BR112018007161B1 (en) | 2015-10-09 | 2024-01-16 | Galapagos Nv | PYRAZOLO[3,4-b]PYRIDIN-6-CARBOXAMIDE N-SULFONYLATED COMPOUNDS, PHARMACEUTICAL COMPOSITION CONTAINING SAID COMPOUNDS AND USES THEREOF TO TREAT CYSTIC FIBROSIS |
| US9873541B2 (en) | 2015-12-24 | 2018-01-23 | Connecticut Container Corp. | Rapid assembling container |
-
2017
- 2017-10-05 US US15/726,075 patent/US9981910B2/en active Active
- 2017-10-06 JP JP2019518492A patent/JP2019537564A/en active Pending
- 2017-10-06 CA CA3039659A patent/CA3039659A1/en not_active Abandoned
- 2017-10-06 AU AU2017339249A patent/AU2017339249A1/en not_active Abandoned
- 2017-10-06 BR BR112019007039A patent/BR112019007039A2/en not_active Application Discontinuation
- 2017-10-06 EP EP17794779.3A patent/EP3523293B1/en active Active
- 2017-10-06 CN CN201780075081.3A patent/CN110036009A/en active Pending
- 2017-10-06 WO PCT/IB2017/056196 patent/WO2018065962A1/en unknown
- 2017-10-06 MX MX2019004018A patent/MX2019004018A/en unknown
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100184739A1 (en) * | 2004-06-24 | 2010-07-22 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette Transporters |
| WO2008147952A1 (en) * | 2007-05-25 | 2008-12-04 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| WO2009003009A1 (en) * | 2007-06-26 | 2008-12-31 | Enanta Pharmaceuticals, Inc. | Substituted pyrrolidine as anti-infectives |
| US20100168094A1 (en) * | 2008-12-30 | 2010-07-01 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
| US20110230483A1 (en) * | 2010-03-19 | 2011-09-22 | Novartis Ag | Pyridine and Pyrazine derivative for the Treatment of CF |
| CN105531268A (en) * | 2013-05-07 | 2016-04-27 | 加拉佩格斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis |
| CN105658655A (en) * | 2013-08-08 | 2016-06-08 | 加拉佩格斯股份有限公司 | Thieno[2,3-C]pyrans as CFTR modulators |
| WO2016069757A1 (en) * | 2014-10-31 | 2016-05-06 | Abbvie Inc. | Substituted chromanes and method of use |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2019004018A (en) | 2019-11-12 |
| EP3523293B1 (en) | 2021-06-16 |
| JP2019537564A (en) | 2019-12-26 |
| US20180099931A1 (en) | 2018-04-12 |
| US9981910B2 (en) | 2018-05-29 |
| CA3039659A1 (en) | 2018-04-12 |
| EP3523293A1 (en) | 2019-08-14 |
| WO2018065962A1 (en) | 2018-04-12 |
| AU2017339249A1 (en) | 2019-05-02 |
| BR112019007039A2 (en) | 2019-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110036009A (en) | Substituted pyrrolidines and their use in the treatment of cystic fibrosis | |
| TWI809005B (en) | Kras g12c inhibitors | |
| CN105916855B (en) | As substituted 4 of Casein kinase 1 D/E inhibitor, 5,6,7- tetrahydro-pyrazoles simultaneously [1,5-A] pyrazines derivatives | |
| CN104470925B (en) | Imidazo-triazine formonitrile HCN as kinase inhibitor | |
| CN105683188B (en) | The ring pyridinyl derivatives of condensed ring two as FGFR4 inhibitor | |
| TWI675833B (en) | Biaryl inhibitors of bruton's tyrosine kinase | |
| CN104619709B (en) | Imidazopyridine derivatives as TNF active regulator | |
| CN102753555B (en) | Big ring class as factor XI, plasma thromboplastin antecedent A inhibitor | |
| CN114615981A (en) | KRAS G12D inhibitors | |
| JP6602840B2 (en) | Heterocyclic carboxylic acids as activators of soluble guanylate cyclase | |
| CN109563043A (en) | The substituted pyridine of inhibitor as DNMT1 | |
| CN106459003B (en) | Pyrazole amide derivatives | |
| CN110035993A (en) | Substituted pyrrolidines as cftr modulators | |
| CN111954664A (en) | Cystic fibrosis transmembrane conductance regulator and methods of use | |
| CN110088096A (en) | The piperidine derivative of inhibitor as ubiquitin-specific protease 7 | |
| CN105339351A (en) | Arginine methyltransferase inhibitors and uses thereof | |
| TWI739779B (en) | Inhibitors of bruton's tyrosine kinase and methods of their use | |
| CN114585628A (en) | Modulators of cystic fibrosis transmembrane conductance regulator | |
| CN102822165A (en) | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same | |
| CN105612153A (en) | Substituted sulfonamide compounds as TRPA1 conditioner | |
| CN112930347A (en) | Inhibitors of KEAP1-Nrf2 protein-protein interactions | |
| CN109790146A (en) | Medical compounds | |
| WO2021164746A1 (en) | Substituted aryl compound | |
| CN114127080A (en) | Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compounds, and methods of use thereof | |
| TW202417449A (en) | Cdk2 inhibitors and methods of using the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190719 |